I was interested in learning more about vitamin E supplementation to address oxidative stress. Dr. Tan wrote a nice summary of Vitamin E in his book “The Truth about Vitamin E”. Vitamin E is a family of eight separate but related molecules, and that includes four tocopherols (delta, gamma, alpha and beta) and four tocotrienols (also delta, gamma, alpha and beta). For many years, the nutrition world focused on tocopherols because it was discovered first. Only in the last decade did tocotrienols start to shine in its delta and gamma molecules and it was found that combined with a healthy lifestyle, it can lower lipids, reduce inflammation, protect the liver, promote bone health, facilitate in eradicating cancer cells and increase survival in cancer patients. In fact, studies demonstrate that the “wrong” form of vitamin E (tocopherols) can actually hinder the body’s ability to absorb the “right form” (tocotrienols).
A few interesting things about tocotrienols:
- Delta tocotrienol help maintain the membrane integrity of the cell membrane to protect cellular functions. Phospholipids, cholesterol and a small amount of protein make up most of the cell membrane, creating a lipid bilayer which is important for water, oxygen and CO2 to cross the membrane while blocking out other larger potentially harmful substances
- It can protect the cell from free radical damage
- Antioxidants like vitamin E (C, A, and selenium and zinc) can give the free radical its own electron without destabilizing the cell. Others include resveratrol, curcumin, astaxanthin, lutein, Coq10. Tocotrienols are well suited to protect the cell membrane because their perfect fit into the lipid bilayer allows them to better protect the lipids within this bilayer from oxidation.
The delta- and gamma-tocotrienols spread out and attach themselves to a variety of cell membranes throughout your body and then start patrolling for free radicals. As soon as they sense one closing in (meaning the free radical attaches to a fatty acid in the cell wall), the tocotrienol molecule releases an electron which re-attaches to the free radical, making the damaged (oxidized) fatty acid in the cell wall whole again. The free radical is stable again and leaves the cell. Put simply, the tocotrienol removes the dysfunctional oxygen from the fatty acid.
What is the difference between tocotrienols and tocopherols? First, they are 40-60 times more potent.
Here are some key differences:
- Tocotrienols have shorter tails that do not anchor deeply into the cell membrane- which allows them to move around the cell 50x faster to intercept free radicals more easily. In contrasts to tocopherols that have a longer tail, anchor deeply into cell membranes, and move more slowly. Because of this it is thought that tocotrienols are 40-60x better at giving one of their electrons to invading free radicals and repairing damage to lipids on membranes
- Tocotrienols have a smaller head and delta tocotrienols have the smallest- allowing them to squeeze in parts of the cell easier, giving them wider access to membranes and increasing their ability to capture more free radicals
- Tocotrienols have unsaturated tails where tocopherols have saturated tails- making them unique in that they have double bonds in their tails and can provide more lipid oxidation protection because of superior bioavailability to cell membranes.
I also want to point out that tocotrienols are great for reducing chronic inflammation. Studies demonstrate that alpha, gamma and delta tocotrienols strongly inhibit NFkB and TNF-a, along with other pro-inflammatory cytokines. “Among the most notable biomarkers to be affected by a 250 mg tocotrienol daily dosage were C-reactive protein (CRP; a predictor for chronic inflammation), nitric oxide (NO), and malondialdehyde (MDA), with decreases of 40%, 40%, and 34%, respectively” (Barrie, nd).
Tocotrienols can increase total antioxidant status. Total antioxidant status also increased by 22%, suggesting that delta-tocotrienol can potentiate endogenous antioxidants. This is great news for the use of tocotrienols for reduce inflammation associated with high cholesterol, CV disease, metabolic syndrome, nonalcoholic fatty liver disease, diabetes and pre-diabetes. It also can play a role in cancer, bone and brain health.
Tocotrienols area great for eye health. Interestingly, delta-tocotrienols may also delay the beginning of cataracts when applied to the eye due to reduced oxidative stress and nitrosative stress to the lenses which are exposed to environmental oxidants. Tocotrienol had a beneficial effect on lens antioxidant enzymes, including superoxide dismutase and catalase, both of which returned to normal levels with the topical treatment. Furthermore, tocotrienol significantly decreased malondialdehyde, a lipid peroxidation end product found to be high in cataracts, and restored the lens soluble to insoluble protein ratio to normal levels.
And finally, it has positive influence on the immune system. One study showed that annatto tocotrienol combined with antibiotics had the greatest efficacy in decreasing bacteria when compared with tocotrienol or antibiotic treatment alone (Tan, n.d). This may be due to an influence that tocotrienols have on T cells.
References
Tan, Barrie. The Truth about Vitamin E: The Secret to Thriving with Annatto Tocotrienols . Kindle Edition.
Zinc is a very interesting mineral. It is also one I commonly see low in hair tissue mineral analysis (HTMA).
It plays an important role in facilitating hundreds of biochemical reactions. Due to its role in enzymatic function, it can impact metabolic pathways such as carbohydrate, protein, nucleic acid, and lipid metabolism. It is also a structural component in thousands of transcription factors and can affect gene expression that impacts many physiological processes in the body. “Zinc appears to be part of more enzyme systems than all the rest of the trace minerals combined; over 300 enzymes from every enzyme class (oxidoreductases, hydrolases, lyases, isomerases, transferases, and ligases) require zinc” (Gropper, n.d.). Some of these zinc dependent enzymes include:
- Carbonic anhydrase: acid base balance- found in erythrocytes and renal tubule cells, essential for maintaining acid-base balance/buffering and respiration. The enzyme catalyzes the reaction that allows rapid disposal of carbon dioxide. Activity of this enzyme in red blood cells diminishes with chronic low zinc status in the diet.
- Alkaline phosphatase: Contains four zinc atoms per enzyme molecule, in which two are required for enzyme activity. This enzyme is found in bones and the liver.
- Alcohol dehydrogenase: contains 4 zinc molecules per enzyme molecule, two are required for catalytic activity. This enzyme is important in the NADH-dependent conversion of alcohols to aldehydes. For example, this enzyme converts retinol (form of Vitamin A) to retinal, which is needed for night vision. It also is required for acetyl aldehyde for alcohol metabolism
- Carboxypeptidases A and B and Aminopeptidases- which is involved in protein digestion. These enzymes are secreted by the pancreas into the duodenum. Zinc is bound tightly to carboxypeptidases and is essential for enzymatic activity; in fact, enzyme activity decreases with zinc deficiency (Gropper, n.d.). Aminopeptidases consist of a group of enzymes also involved in protein digestion which contains 1-2 zinc atoms for catalytic activity.
- Delta (Δ)-Aminolevulinic Acid Dehydratase: Heme Synthesis- needed for heme synthesis is zinc dependent. Interestingly, lead when present in the body in high concentrations can replace zinc in the dehydratase and diminishes heme synthesis.
- Superoxide dismutase (SOD1)- an antioxidant found in the cell cytosol requires two atoms of zinc (and two copper) to function. An extracellular form of the enzyme (SOD3) that is also zinc and copper dependent has been characterized and appears to be more sensitive to zinc than is the cytosolic form of the enzyme. Both the cytosolic and extracellular forms of superoxide dismutase serve important antioxidant defense roles in the body by catalyzing the removal of superoxide radicals, O2
- Phospholipase C-this enzyme hydrolyzes the glycerophosphate bond in phospholipids (a structural component of cell membranes!). It requires 3 zinc atoms for catalytic activity.
- Matrix Metalloproteinases-The matrix metalloproteinases are zinc containing endopeptidases (zinc is located in the catalytic site where substrate binds). They generally function in wound healing, degrading components of the extracellular matrix (among other roles) to allow for remodeling of extracellular matrix proteins and tissue repair
- Polymerases, Kinases, Nucleases, Transferases, Phosphorylases, and Transcriptases- Nucleic Acid Synthesis and Cell Replication and Growth Polymerases, kinases, nucleases, transferases, phosphorylases, and transcriptases all require zinc.
- Gene expression- Zinc plays a major structural role in regulating gene transcription by promoting a confirmation change in the shape of the transcription factor protein. You may have heard the term zinc fingers which is often used to indicate the secondary shape (configuration) of the transcription factor proteins when bound to zinc.
In addition to the above roles, zinc helps maintain cell membranes through multiple actions on membrane proteins including direct effects on membrane proteins’ conformation, on protein-to-protein interactions, and on other membrane components
Zinc itself also is believed to stabilize membrane structure by stabilizing phospholipids and thiol (SH) groups in enzymes and membrane proteins that need to be maintained in a reduced state.
Zinc may also stabilize membranes by quenching free radicals as part of metallothionein and by promoting associations between membrane skeletal and cytoskeletal proteins
Additionally, zinc in cells is found bound to tubulin, a protein that makes up the microtubules. Microtubules are thought to act as a framework for structural support of the cell as well as enable movement.
Zinc is also involved with insulin and thus influences carbohydrate metabolism. Zinc is transported into pancreatic b-cells by zinc transporter ZnT8, which also enables uptake into secretory vesicles. Pancreatic b-cells are responsible for insulin production and secretion (Gropper, n.d.).
Zinc can also influence the basal metabolic rate (BMR). A decrease in thyroid hormones and basal metabolic rate has been observed with consumption of a zinc-restricted diet (Gropper, n.d.).
Zinc is also important for taste; it is a component of gustin, a protein involved in taste acuity (Gropper, n.d.).
Cell mediated and humoral immunity are also influenced by zinc. T-cells are critical to immune system function and with zinc deficiency, thymulin activity diminishes and profoundly affects T-cell numbers and functions, and pre-T-cell apoptosis (programmed cell death) (Gropper, n.d.).
Deficiency symptoms
Some signs and symptoms of deficiency in adults include anorexia, diarrhea, lethargy, depression, skin rash/ lesions/dermatitis, hypogeusia (blunting of sense of taste), alopecia (some hair loss; remaining hair make take on a reddish hue), vision problems, and impaired immune function, protein synthesis, and wound healing (Gropper, n.d.).
Zinc deficiency can be associated with decreased mobilization of retinol from the liver (even with adequate liver vitamin A stores) as well as decreased plasma retinol-binding protein concentrations (Gropper, n.d.).
An overall deficiency of zinc stores within the body has been implicated in the systemic susceptibility of infection and in the pathogenesis of some cancers (Liu et al., 2011)
Zinc also demonstrates an important role within the lumen of the alimentary canal, as evidenced on the observations that supplementation of oral diets with Zn2+ has beneficial effects on diarrhea and inflammatory conditions of the gastrointestinal tract (Liu et al., 2011). “In gastric mucosa, adequate intracellular stores and luminal content of Zn2+ may regulate integrity of and acid secretion by the gastric glands and enhance protection of the mucosa as a whole against acid-peptic injury (Liu et al., 2011).
Measuring deficiency
Evaluating zinc nutriture is difficult, owing to homeostatic control of body zinc. A variety of indices have been used to assess zinc status, including measurements of zinc in red blood cells, leukocytes, neutrophils, and plasma or serum.
The most common basis for assessment is serum or plasma zinc, with fasting concentrations less than about 70 µg/dL (10 µmol/L) suggesting deficiency. A cutoff of 50 µg/dL, however, may better predict clinical signs of zinc deficiency (Gropper, n.d.). Plasma zinc concentrations range from about 70 to 120 μg/dL (10–18 µmol/L), with plasma containing about 3 mg of zinc. Plasma zinc concentrations decrease after eating, as well as under conditions of infection and trauma
Low fasting plasma zinc concentrations indicate that little zinc is present in the exchangeable zinc pool and may reflect a loss of tissue zinc (especially from the liver). Plasma zinc concentrations, however, must be interpreted with caution because concentrations are influenced by many factors unrelated to zinc depletion, including meals, time of day (diurnal variation), stress, infection, and medications such as steroid therapy. In fact, postprandial (after eating) plasma zinc concentrations have been found to be more sensitive to low dietary zinc intake than fasting plasma zinc concentrations (Gropper, n.d.)..
Metallothionein has also been used to assess zinc status. Concentrations of metallothionein respond to changes in dietary zinc. For example, liver and red blood cell metallothionein concentrations diminish as dietary zinc intake decreases and are thought to reflect zinc status or stores (Gropper, n.d.).
Serum zinc and serum metallothionein concentrations can be used to indicate poor zinc status if both are low. Elevations in serum metallothionein coupled with low serum zinc, however, usually suggest an acute-phase response, and in such conditions these indices are not reliable. Urinary zinc excretion remains fairly constant over a range of intakes and is thought to be a useful marker of status in those with moderate to severe zinc deficiency (Gropper, n.d.)..
Low hair zinc may be associated with chronic intake of dietary zinc in suboptimal amounts; however, the concentration of zinc in hair depends not only on delivery of zinc to the root but also on the rate of hair growth, which is affected by other conditions (including protein status)(Gropper, n.d.).
.Measurement of the activity of zinc-dependent enzymes has also been employed as an index of zinc status. Studies using enzymes as indicators typically have measured carbonic anhydrase or alkaline phosphatase, which “hold” zinc less securely than other zinc metalloenzymes.
Ideally, measurements of activity should be taken before and after zinc supplementation (Gropper, n.d.)..
Supplementation
Supporting deficiency in adults typically requires oral zinc supplementation; doses of 10–20 mg/day are recommended. Although higher doses (often up to 50 mg given two to three times per day) may be prescribed, use of such doses is more likely to impair copper status.
Some population groups—especially older adults, vegetarians, and those with alcoholism and with limited income—have been found to consume less than adequate amounts of zinc.
Alcohol ingestion additionally reduces intestinal zinc absorption and increases urinary zinc excretion.
Additional conditions associated with an increased need for intake include trauma, sickle-cell anemia, and disorders causing malabsorption such as Crohn’s disease, short bowel syndrome, celiac disease, and liver failure, as well as surgical bariatric procedures, especially Roux-en-Y gastric bypass and duodenal switch, used to treat obesity. Diarrhea and intestinal fistulas also substantially increase fecal zinc losses; supplementation with up to 20 mg of zinc/day may be needed under such conditions.
ZINC and COPPER
The detrimental effect of excessive zinc intake on copper absorption is thought to be attributable to zinc’s stimulation of the synthesis of metallothionein, which has a higher affinity for copper than for zinc. With increased intestinal concentrations of metallothionein induced by high zinc levels, ingested copper readily binds to the metallothionein within the enterocyte and becomes “trapped,” preventing its passage into the plasma. The increased risk of copper deficiency precipitated by zinc supplementation led to the Tolerable Upper Intake Level for elemental zinc of 40 mg daily.
Other considerations
Recent reports have begun to explore the mechanisms that regulate cellular homeostasis of Zn2+ in mucosal cells of the gastrointestinal tract (Liu et al., 2011)
There is a relationship to zinc uptake is dependent on intracellular Ca2+ stores.According to Liu et al (2011), baseline conditions, uptake of Zn2+ across the basolateral membrane depends on adequate stores of intracellular calcium ion (Ca2+) . With stimulation by powerful agonists such as forskolin and carbachol, demand for extracellular Zn2+ increases and depends on influx of extracellular Ca2+ .
“In the current set of studies, we find that Ca2+ facilitates optimal uptake of Zn2+ across the cell membrane, implying that it is either a counter-ion in exchange or it is acting as a regulatory second messenger. Membrane proteins that facilitate Zn2+ transport constitute the SLC30A (ZnT) and SLC39A (Zip) gene families” (Liu et al., 2011).
Diminished calcium absorption has been observed with the ingestion of zinc supplements when calcium intake is low (<300 mg/day of calcium). However, calcium absorption appears to be unaffected by zinc when calcium intake is at adequate (recommended) levels.
Cadmium, if present in high concentrations in the body, appears to bind to sites to which zinc would normally bind and thus disrupts normal zinc functions. For example, cadmium can replace zinc in zinc fingers, preventing the fingers from functioning as they would with zinc present.
Zinc is found in foods complexed with nucleic acids and with amino acids that are part of peptides and proteins. The zinc content of foods varies widely.
Very good sources of zinc are red meats (especially organ meats) and seafood (especially oysters and mollusks). Other relatively good animal sources of zinc include poultry, pork, and dairy products. Animal products are thought to provide 40–70% of zinc consumed by most people in the United States.
Whole grains and legumes also provide moderate amounts of zinc.
Cereals, some of which may be fortified, are thought to provide about 30% of the zinc in the U.S. diet. Fruits contain little zinc.
Plant sources, however, not only have lower zinc contents, but zinc from plants is also absorbed to a lesser extent than zinc from animal sources (e.g., meat).
Absorption
Zinc absorption is enhanced with:
Ligands or chelators including organic acids (like citric acid and picolinic acid) and prostaglandins may bind and promote zinc absorption
Glutathione and products of protein digestion, such as amino acids, serve as ligands (such as sulfur, cysteine, or nitrogen). Interestingly, amino acids serving as ligands help maintain zinc’s solubility in the gastrointestinal tract
Zinc inhibition:
Absorption of zinc is also enhanced by an acidic environment. Thus, the use of medication such as antacids, H2 receptor blockers (such as Zantac [ranitidine], Tagamet [cimetidine], or Pepcid [famotidine]), and proton pump blockers (such as Prevacid [lansoprazole] or Prilosec [omeprazole]), which are commonly taken to treat heartburn, gastroesophageal reflux disease, and ulcers, increases gastric and proximal intestinal pH and decreases zinc absorption
Phytic acid found in plant foods, particularly legumes, lentils, nuts, seeds, and whole-grain cereals decrease absorption
Other minerals such as iron and calcium negatively impact absorption
References
Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P.. Advanced Nutrition and Human Metabolism (Page 509). Wadsworth Publishing. Kindle Edition.
Liu, J., Kohler, J. E., Blass, A. L., Moncaster, J. A., Mocofanescu, A., Marcus, M. A., . . . Soybel, D. I. (2011). Demand for Zn2+ in acid-secreting gastric mucosa and its requirement for intracellular Ca2+. PLoS ONE, 6(6), e19638. doi:10.1371/journal.pone.0019638
The relationship between thiamine and diabetes mellitus (DM) has been reported in the literature (Luong & Nguyen, 2012). Thiamine acts as a coenzyme for transketolase (Tk) and for the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. These enzymes play a fundamental role for intracellular glucose metabolism by increasing Krebs cycle activity (Luong & Nguyen, 2012). Low thiamine has been reported to be decreased by 76% in T1D and 75% in T2D patients, as evidenced by low blood thiamine levels, erythrocyte transketolase activity and high erythrocyte thiamine pyrophosphate (TPP).
Additionally, thiamine transporter protein concentration has been shown to be increased in erythrocyte membranes of T1D and T2D patients. “Therefore, changes in thiamine levels may be masked by an increase in thiamine transporter expression” (Luong & Nguyen, 2012). The low thiamine values in diabetic patients might also be a reduced apo-enzyme level from the disease itself rather than thiamine deficiency (Luong & Nguyen, 2012)
I think it is important to mention, there are four distinct biochemical pathways that have been identified as mechanisms in which intracellular hyperglycemia can promote some of the complications of diabetes (such as vascular damage, renal impairment, neurological damage and endothelial damage in the retina) (Brownlee, 2005). These include: increased flux through the polyol pathway, formation of AGE’s, activation of protein C kinase pathway and increase flux through hexosamine biosynthetic pathway. I will briefly discuss each below (Luong & Nguyen, 2012).
- Polyol pathway- This pathway focuses on the enzyme aldose reductase, which is responsible for reducing toxic aldehydes in the cell to inactive alcohols. But when the glucose concentration is too high in the cell, aldose reductase reduces the glucose to sorbitol. NADPH is used to drive this reaction forward, but it runs the risk of being overconsumed in this process. When there is elevated blood glucose and energy overload in the cell, we start to waste NADPH which is essential for regeneration of GSH. When we are running through this pathway, it can cause a glutathione deficit in the cell, which is why sometimes diabetes is associated with GSH deficiency. By reducing the amount of reduced glutathione, the polyol pathway can increase susceptibility to intracellular oxidative stress (Luong & Nguyen, 2012).
- Intracellular production of AGE precursors. AGE’s are toxic compounds deriving from non-enzymatic glycoxidation reactions of reducing sugars with proteins, which then result as being structurally and functionally compromised. Protein glycation occurs in vivo in physiological conditions as a post-translational modification that takes place slowly and continuously during the life span, driving AGE accumulation in tissues during aging. AGE’s have been associated with age related conditions such as diabetes and insulin resistance. In addition, accumulation of AGE’s is accelerated leading to other conditions (Aragno & Mastrocola, 2017).
- Activation of the protein Kinase C pathway- High levels of fatty acids and hyperglycemia activate DAG, which turns on PKC. This promotes various processes that results in decreased nitric oxide (NO) bioavailability. Reducing NO availability and produces oxidative stress in the nervous and vascular system, and reduce ability to synthesize NO which can increase oxidative stress(neuro and vascular) and reduce the ability to synthesize NO which can increase vasoconstriction, poor blood flow and oxygenation of tissue (Roberts & Porter, 2013).
- Hexosamine pathway– Chronic high blood pressure can upregulate this pathway. Fructose 6-P is transformed to glucosamine 6-P by the enzyme glutamine fructose 6-P amidotransferase (GFAT). Glucosamine then promotes the synthesis of uridine diphosphate-N-acetylhexosamine (UDP-GlcNAc) that then serves as a substrate for N- or O-glycation of numerous proteins (Luo, Wu, Jing, & Yan, 2016). “This posttranslational modification can enhance glucotoxicity by impairing protein function and has been demonstrated to be involved in insulin resistance and pathogenesis of diabetes” (Luo et al., 2016). If transketolase activity is low, it is likely that fructose 6 pathway will go through hexosamine pathway, instead of the pentose phosphate pathway which thiamine is a cofactor.
Diabetics are associated with tissue specific thiamine deficiency. This is often demonstrated by: a marked decrease of plasma thiamine concentration; decreased activity of the thiamine-dependent enzyme of transketolase (TK); decreased levels of TK protein in renal glomeruli linked to a profound increase in renal clearance of thiamine (Thornalley et al., 2007). According to Thornalley et al (2007), diabetics are statically more likely to be more thiamine deficient since they waste it through kidneys making their requirement higher.
Insulin deficiency is also associated with reduced rate of thiamine transport across the intestine. High prevalence of low plasma concentrations is prevalent in patients with T1 and T2 diabetes, associated with thiamine clearance
What all this means?
Transketolase acts as a bridge between PPP and glycolytic pathway requiring B1 as a cofactor. Thiamine deficiency slows down transketolase. With thiamine, the pentose phosphate pathway can take the extra intermediates of the glycolytic pathway until we need to make more energy. When there is thiamine deficiency, we are unable to effectively shunt these intermediates down the pentose phosphate pathway( PPP), we end up with build up of intermediates. When this energetic block occurs, such as in mitochondrial dysfunction, the intermediates are shunted into alternative pathways. These yield inflammatory products, and it is the products of these pathways that are central in the damage caused by diabetes or involved in diabetic complications.
In diabetes, there is an overload of energy, which causes reverse the electron flow which can then increase reactive oxygen species. Decreased availability of thiamine in vascular cells in diabetes exacerbates metabolic dysfunction in hyperglycemia (Thornalley et al., 2007). These yield inflammatory products as indicate above, and it is the products of these pathways that are central in the damage caused by diabetes or involved in diabetic complications.
It is thought that thiamine supplementation is helpful in diabetes. Thiamine supplementation can reduce AGE formation, reduce flow through hexosamine and polyol pathway, reduce protein kinase C activity, inhibits NF-KB activation and normalize markers associated with methylglyoxal and glycation.
High dose supplementation as befothiamine and thiamine hydrochloride possess antioxidant properties, reduces lipid peroxidation, reduces oxidative stress associated with diabetes and activates eNOS (EONutrition, 2019). It may also improve endothelial dysfunction in a hyperglycemic state. In addition, it may improve pain associated with diabetic polyneuropathy and reduce urinary albumin excretion, reducing renal AGE’s and oxidative damage (EONutrition, 2019).
References
Aragno, M., & Mastrocola, R. (2017). Dietary Sugars and Endogenous Formation of Advanced Glycation Endproducts: Emerging Mechanisms of Disease. Nutrients, 9(4). doi:10.3390/nu9040385
Brownlee, M. (2005). The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 54(6), 1615-1625. doi:10.2337/diabetes.54.6.1615
EONutrition (2019). Retrieved (2020, June 22) from https://www.youtube.com/watch?v=m3DopqTz1Q4&t=801s
Luo, X., Wu, J., Jing, S., & Yan, L. J. (2016). Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity. Aging Dis, 7(1), 90-110. doi:10.14336/ad.2015.0702
Luong, K. V., & Nguyen, L. T. (2012). The impact of thiamine treatment in the diabetes mellitus. J Clin Med Res, 4(3), 153-160. doi:10.4021/jocmr890w
Roberts, A. C., & Porter, K. E. (2013). Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diab Vasc Dis Res, 10(6), 472-482. doi:10.1177/1479164113500680
Thornalley, P. J., Babaei-Jadidi, R., Al Ali, H., Rabbani, N., Antonysunil, A., Larkin, J., . . . Bodmer, C. W. (2007). High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia, 50(10), 2164-2170. doi:10.1007/s00125-007-0771-4
It is no secret that exercise is very important for optimal health. But many people still do not see the connection and it seems to be a low priority for them when it comes to managing their health. However, I realize that many people truly do not understand how important it really is, even from the perspective of glycolytic pathway, so I want to take the time to summarize it here. Exercise is known to stimulate glycogenolysis, especially when it is conducted first thing in the morning after an overnight fast. In fact, I often tell my clients to do their exercise fasted when they want to optimize weight loss. But how does it work?
Before I review that, I want to do a quick summary of biochemistry.
In our muscles, glycogen supplies glucose-6-phosphate for ATP synthesis in the glycolytic pathway. Any enzyme known as glycogen phosphorylase in the muscle is stimulated during exercise by the increase of AMP and by phosphorylation. The phosphorylation is stimulated by calcium released during contraction and by epinephrine, the fight or flight hormone, as well as hypoglycemia during stressful situations or exercise where there is an immediate need for glucose. It is important to understand that liver glycogen stores are principally for the support of blood glucose during fasting or extreme need such as exercise, and the degradative and biosynthetic pathways are regulated principally by changes in the insulin/glucagon ratio and by blood glucose levels. The key point to remember is that muscle glycogenolysis is regulated principally by AMP, which signals a lack of ATP, and by Ca2+ released during contraction. Epinephrine, which is released in response to exercise and other stress situations, also activates skeletal muscle glycogenolysis.
Let’s take a practical look at what happens when someone begins to contract their muscles during exercise. If someone were to immediately begin running as fast as possible, the following cascade would take place.
- Within 3 seconds, muscle cells exhaust stored ATP.
- As exercise continues, this ATP must be regenerated, so the ATP–PCr system kicks in to shoulder most of the load. This lasts for about 10 seconds. And because time is required for ATP to be regenerated, you start to slow down a bit.
- As exercise continues and the ATP–PCr stores are depleted, the glycolytic system will begin to provide most of the energy transfer for ATP regeneration. This lasts for about 90 to 120 seconds or so, depending on the intensity of the exercise. Since the glycolytic system generates ATP more slowly than the ATP–PCr system, again, you have to slow down a bit more.
- If exercise continues beyond this time frame, the oxidative system will start to provide most of the energy transfer for ATP regeneration. And again, because the oxidative systems are slower than the anaerobic systems, the pace must slow again. In fact, if the pace is slow enough, the exercise can last for quite a long time.
There are two main types of exercise: anaerobic exercise and aerobic exercise. Anaerobic exercise is defined as higher-intensity, shorter-duration (less than 2 minutes) activity, whereas aerobic exercise occurs when the exercise is longer than 2 minutes in which the oxidative system must kick in to provide the remaining energy for ATP regeneration. As our initial energy stores can only supply energy for about three seconds, our ATP must be regenerated in large amounts, and quickly, to support this type of exercise.
Short-burst activities such as the following:
- The golf swing
- Field events (shot put, discuss)
- Gymnastics
- The tennis swing
- The 100-meter sprint
- The baseball swing
- Diving
Oxidative energy transfer takes place in the mitochondria of our cells and utilizes a combination of muscle glycogen, intramuscular fatty acids, free fatty acids, and amino acids. As the oxidative processes utilize breakdown products from both glycolysis (glucose through to pyruvate) and beta oxidation (fatty acids through to acetyl-coA), energy transfer occurs at a slower rate. However, what this system lacks in speed, it makes up for in ATP regeneration. As a result, oxidative metabolism can support activities including the following:
- 800-meter run
- 2000-meter rowing
- 1500-meter skating
- Cross-country skiing
- Jogging
- Walking
- Long-distance swimming
Indeed, any activity done at a high intensity for longer than two minutes derives a large percentage of its energy transfer from the oxidative system. There is a “switchover point” at which an activity moves from anaerobic to aerobic, as seen in this interesting comparison.
- 200-meter run: 29% aerobic; 71% anaerobic
- 400-meter run: 43% aerobic; 57% anaerobic
- 800-meter run: 66% aerobic: 34% anaerobic
- 1500-meter run: 84% aerobic; 16% anaerobic
The primary muscle fiber types that contribute to aerobic exercise are the oxidative type I and type IIA fibers. As aerobic exercise is heavily oxygen dependent, training adaptations occur in order to support oxygen transport and delivery in these fibers. Specifically, aerobic exercise can increase the number and size of the blood vessels. This occurs through increased capillarization. Specifically, with aerobic training, there is a greater number of capillaries per unit of muscle. This allows for enhanced delivery of oxygen (fuel) to muscle cells, enhanced removal of CO2 and waste products, and the transfer of heat away from the muscle. In addition to enhanced oxygen delivery, there is an increase in the size and number of mitochondria along with greater myoglobin content within cells. While the greater capillarization leads to more oxygen transport, the greater myoglobin leads to increased muscle oxygen uptake, and the larger and more numerous mitochondria allow for greater oxygen use. Of course, in addition to these adaptations, the enzymes involved with aerobic energy transfer will adapt as well.
Let’s talk a bit about oxygen and the adaptations that occur with regular exercise.
After a full exercise session, or even after a single interval within an entire exercise session, the oxygen deficit that’s accumulated must be paid back. This means that after you’ve stopped exercising and the amount of mechanical work you’re doing is no different than you’d be doing at rest, you still continue to consume more oxygen. This period of increased oxygen consumption and energy demand has been called the period of oxygen debt or EPOC (excess post-exercise oxygen consumption). In essence, after exercise, the amount of oxygen consumed can be elevated for minutes to hours. This is due to the fact that the body must:
- a) metabolize additional nutrients,
- b) replenish the energy stores that have been used up, and
- c) reload the depleted oxygen stores in the muscle and blood.
In addition to these recovery-type activities, the following also contribute to the EPOC:
- Elevated post-exercise body temperature
- Increased activity of the heart and respiratory muscles
- Elevated levels of metabolism-boosting hormones
- Increased conversion of energy transfer products such as lactate into other substrates
- Increased protein synthesis
- Recovery of muscles stressed and damaged with the activity
It is important to note, however, that the energy systems do not work independently from one another. During various types of exercise, from aerobic to anaerobic, all three energy systems are activated. However, the extent to which they are activated, and the amount of ATP they regenerate relative to the total ATP regeneration required, determines the description of the activity. For example, during short-burst activity, the ATP–PCr system is most important. When immediate and explosive movement is desired, the brain initiates the contraction with a signal that’s passed along the nerves to the muscles. The muscles then contract, using ATP and depleting these immediate energy stores within a second or two. In order for the muscles to continue to contract, the resulting ADP and P must be regenerated to ATP.
Adaptations to Exercise.
In response to regular exercise training, whether anaerobic or aerobic, certain changes occur in the muscle. These changes improve the body’s ability to respond to similar exercise challenges in the future. Each of these processes is regulated by protein synthetic mechanisms initiated within our genetic material (our DNA). Cellular communication through hormones is intimately involved in this process. The hormone insulin, in the presence of adequate nutrient availability, encourages the stimulation of protein synthesis and a positive nitrogen balance. Insulin availability is greatest during well-fed conditions and during periods of energy surplus. Protein and amino acid intake is key here as protein-containing meals stimulate a positive protein status. In addition, hormones like testosterone and growth hormone have a stimulatory effect on muscle adaptation.
On the other hand, the counter-regulatory hormones such as glucagon, catecholamines, and glucocorticoids have a contradictory effect, promoting protein breakdown and a negative nitrogen balance. These hormones are released in large numbers during periods of fasting or energy deficit
Protein synthesis and exercise adaptation are also affected by:
- The amount of mRNA in our cells
- Ribosomal number
- Ribosomal activity
- Amino acid availability
- The hormonal environment
- Our native genetic code
Interestingly, even the process of recovering and adapting to our exercise training demands is metabolically costly. As proteins are degraded and amino acids re-synthesized into proteins, this process of protein turnover builds more functionally adapted enzymes, contractile units, etc. And this process accounts for between 10% and 25% of resting energy expenditure. Therefore, as you can see, not only does exercise increase total daily energy expenditure during the activity, it also increases post-exercise expenditure through two mechanisms. Energy expenditure is increased due to both the oxygen debt being paid back and to the increased protein turnover and synthesis just described.
Adaptations of anerobic exercise such as weight training and sprint training:
- muscle fibers both increase in size and in myofibrillar number
- mitochondrial size and number
- increases in myoglobin number
- increases in intracellular storage capacity and availability (such as stored glycogen)
- increases in intracellular glycogen storage can also contribute to muscle hypertrophy
- In addition to changes in muscle cross-sectional area, anaerobic exercise can enhance the activity of ATP–PCr system enzymes (creatine kinase, myokinase) and the glycolytic system enzymes (glycogen phosphorylase, phosphofructokinase).
These changes help to increase the rate of energy transfer within the muscle, allowing for more rapid responses to energy demands in the future.
Adaptations to aerobic exercise such as jogging, steady state cardio or swimming:
Please note, this type of lower-intensity, longer-duration activity primarily influences muscle quality (as opposed to muscle size).
- Enhancement of oxidative or mitochondrial enzyme activity
- Increase in intramuscular glycogen and triglyceride content
- Increase in blood volume due to increase uptake and delivery of aerobic activity- due to increase in red blood cell content and the oxygen-carry capacity of the body.
- Capillary density of trained muscles increases- meaning there will be a great number of capillaries per muscle fiber
- With this lengthened border between blood vessels and muscle fibers, oxygen delivery, carbon dioxide removal, waste removal, fuel delivery to muscle, and the transfer of heat are all amplified.
- Beyond this, the myoglobin content of skeletal muscles will increase, improving oxygen delivery across muscle cells
- Finally, the number and size of mitochondria are increased with aerobic activity of high enough intensity. This promotes greater oxygen utilization through the process of pyruvate, fatty acid, and ketone utilization through the Krebs cycle and electron transport chain
Additional benefits of both aerobic and anaerobic exercise training include:
- The attenuation of sympathetic nervous system activity.In essence, “stress” to the body with exercise is minimized over time, and therefore greater workloads are required to promote the same amount of adaptation.
- Greater insulin sensitivity.With exercise training, the body responds to carbohydrate intake with less insulin release, allowing insulin to act in carbohydrate update and protein synthesis without preventing fat loss/stimulating fat gain.
- Improved fatty acid uptake and transport.Another positive response to exercise training is that fats can be more easily mobilized from adipose tissue, transported, taken up, and broken down.
- Less lactate produced per intensity.At every intensity, less lactate will be produced. This is due to greater aerobic production of ATP at every intensity, lower catecholamine response, reduced carbohydrate metabolism, and changes in the isoenzymes of lactate dehydrogenase to forms that favor the conversion of lactate to pyruvate.
- More lactate removed per unit of intensity.At every intensity, more lactate will be removed. Increased rates of lactate removal are due to increased blood flow to the liver and enhanced uptake of lactate by cardiac and skeletal muscles.
- Better lactate tolerance.With training at the highest intensities, the body can better deal with high acid conditions and high levels of lactate. This means higher intensities can be achieved and sustained for short periods of time.
sympathetic nervous system: One division of the autonomic nervous system that is always active and provides sympathetic tone. Its activity increases during times of bodily stress.
So, what qualifies as “intense exercise”? Resistance training (strength training), interval training(through activities such as running, climbing, cycling, and rowing), circuit training, rope jumping, running hills, squat thrusts, plyometrics, explosive medicine ball work, explosive kettlebell exercises, and strongman activities are all high-intensity activities.
Basically, high-intensity activity includes any physically demanding task that:
- a) incorporates many muscle groups, and
- b) is done near your maximum heart rate.
The high-intensity activities listed above require a maximum of muscle activity, which leads to high amounts of cellular stress and the need for muscle adaptation. It’s this muscle stress and adaptation that brings about the maximum number of benefits, including increased protein turnover, muscle preservation and building, a high energy cost, and even cardiovascular benefits.
However, as important as exercise is to this process, nutrition is equally critical.
Firstly, nutritional status can impact energy transfer. Therefore, a good nutrition program will help facilitate top performance of each of the energy systems: ATP–PCr, glycolysis, and oxidative phosphorylation. Both macronutrients and micronutrients are important here.
A sub-optimal nutritional intake can reduce enzyme efficiency (due to deficiencies of co-enzymes and co-factors) and lead to substrate deficiencies. And this means poor exercise performance and fewer calories burned both at rest and during exercise. So much for the metabolic and muscle preserving and building benefits of exercise. In addition, with an inadequate intake of dietary protein and fat, amino acid availability and the ratio of anabolic to catabolic hormones can be compromised. This can lead to an inability to build and preserve muscle mass, even in the face of a solid exercise program.
For more information on how IC Healer can help you , Book a Discovery Call today.
Sign up for my FREE GUIDE
Having worked in the fitness industry for over 15 years and helping people with their weight loss goals, I always wondered what role exercise had on inflammation and aging. In obesity, various mechanisms are thought to contribute to a low- grade inflammation within the fat tissue affecting the development of several secondary diseases of aging such as metabolic syndrome, insulin resistance (IR), diabetes, arterial hypertension, and autoimmune diseases (Schmidt et al., 2015). Most importantly, exercise is demonstrating to help modulate the inflammatory processes associated with aging (inflammaging). Two to four- fold elevations in circulating levels of pro-inflammatory cytokines such as IL-6, TNF-a, and acute phase proteins such as CRP and serum amyloid A (SAA) are typical in the elderly when compared to the young, in the absence of chronic disease. Significant declines in immune function with aging promote inflammation, which can increase the prevalence of conditions associated with “inflammaging” such as hypertension, CV disease, and neurodegeneration. Aging is also associated in increases in circulating levels of reactive oxygen specie (ROS), decline in antioxidant capacity and increase in oxidative stress (Woods, Wilund, Martin, & Kistler, 2012). “While transient inflammation is necessary for recovery from injury and infection, it has been hypothesized that the excessive inflammation in aging may also be caused by an exaggerated acute-phase response that may be a cause or consequence of a delayed recovery from an insult that promotes inflammation” (Woods et al., 2012). This is often seen in failure to completely resolve an immune response or can often been seen in an exaggerated immune response and impaired clearance of the immune mediators.
Exercise has a strong influence on the levels of pro-inflammatory cytokines (Gleeson et al., 2011). In fact there is a strong relationship to BMI that may indicate that the decrease in inflammatory molecules may be related to decrease in visceral fat. Additionally, physical activity may further mitigate inflammation by improving endothelial function, increasing insulin sensitivity, enhancing liver health and increasing blood vessel growth and blood flow.
Various mechanisms are involved in exercise’s role in lowering inflammation, some of them are listed below:
- Reduction in visceral mass-as mentioned early, a reduction in visceral mass has an indirect effect of being able to decrease inflammation, since accumulation of fat in the omentum, liver and muscles, as well as the expansion of adipose tissue, results in enhanced production of certain inflammatory mediators. Therefore loss of visceral fat can result in reduction in inflammation (Gleeson et al., 2011).
- Release of IL-6 from working muscles-A fall in muscle glycogen content with exercise signals the muscles to secrete IL-6 (a pro-inflammatory cytokine), which stays high during the duration of exercise. However, this also initiates a rise in anti-inflammatory cytokines IL-10 and IL-1RA to minimize the effects on the tissue. Also, it was interesting that you really need 2.5 hours or more of strenuous exercise to get a significant elevation of IL-6, which may partially explain why marathon runners may have suppressed immune systems (Gleeson et al., 2011).
- Increased levels of cortisol and adrenaline-IL-6 stimulates the release of cortisol, which is smaller doses, can have anti-inflammatory effects. It should be pointed out that too much cortisol secretion from the adrenal glands can create a chronic state of inflammation as well, so this could also be a dose dependent phenomenon (Gleeson et al., 2011).
- Reduction in oxidative stress-Regular exercise can reduce oxidative stress by up-regulating endogenous anti-oxidant defense systems, mitigating the damage from overproduction of oxidants such as nitric oxide, peroxynitrate and hydroxyl radicals during aging (Woods et al., 2012
- Resistance training can reduce TNF–a-Muscle protein synthesis was inversely related to TNF-a as demonstrated in the effects of TNF-a genes after 3 months of resistnace training (Woods et al., 2012).
- Vagus nerve stimulation– Stimulation of the parasympathetic nervous system via the vagus nerve can inhibit pro-inflammatory cytokine production and protects against systemic inflammation (Woods et al., 2012). “hey referred to this pathway as the “cholinergic anti-inflammatory pathway,” and described it as a central homeostatic mechanism by which the sympathetic division of the autonomic nervous system stimulates the inflammatory response through the release of epinephrine and norepinephrine, while the parasympathetic nervous system works reciprocally to suppress this release of proinflammatory cytokine” (Woods et al., 2012). This is often evidenced by a decrease in heart rate recovery (HRR) and heart rate variability (HRV) since one of the primary functions of the vagus nerve is to control heart rate (Woods et al., 2012).
- Activation of HPA-axis– Exercise can activate the HPA axis and sympathetic nervous system. This can be due to cortisol’s potent anti-inflammatory effects and catecholamines that can inhibit pro-inflammatory cytokines (Woods et al., 2012)..
“In summary, exercise training is known to have beneficial effects across a broad spectrum of organ systems and its anti-inflammatory actions are complicated by the intricate interplay among organs and cytokines” (Woods et al., 2012). Exercise prescriptions are definitely a necessary element in any protocol that involves optimizing health, reducing inflammation and slowing down inflammatory diseases of stress and aging such what this patient is experiencing.
For more information on how IC Healer can help you , Book a Discovery Call today.
Sign up for my FREE GUIDE
References
Gleeson, M., Bishop, N. C., Stensel, D. J., Lindley, M. R., Mastana, S. S., & Nimmo, M. A. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol, 11(9), 607-615. doi:10.1038/nri3041
Part 2 of 2: Inflammation and Exercise: friend or foe? (2011, August 25). Retrieved 2018, May 2 from https://inscientioveritas.org/inflammation-and-exercise/ (Links to an external site.) (Links to an external site.)
Schmidt, F. M., Weschenfelder, J., Sander, C., Minkwitz, J., Thormann, J., Chittka, T., . . . Himmerich, H. (2015). Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS ONE, 10(3), e0121971. doi:10.1371/journal.pone.0121971
Woods, J. A., Wilund, K. R., Martin, S. A., & Kistler, B. M. (2012). Exercise, inflammation and aging. Aging Dis, 3(1), 130-140.
As a fitness instructor, I can really relate to this module. I have been teaching fitness for over 10 years, and have taught all levels of classes from basic cardio classes, HIIT, indoor cycle, and strength classes. In fact, my favorite class I teach is metabolic conditioning, that consists of both higher impact cardio intervals and full body weight training. Due to my extensive experience in the fitness industry, I am a bit biased and believe that all modes of exercise are important for brain health. This includes traditional cardio, interval training and weight training.
Exercise is a promising strategy for combating cognitive decline. According to a study by Nagamatsu et al (2012), both aerobic training and resistance training enhance cognitive performance and functional plasticity in healthy community-dwelling seniors and those with mild cognitive impairment (Nagamatsu, Handy, Hsu, Voss, & Liu-Ambrose, 2012). According to Lucas et al (2015), regular exercise promotes angiogenesis, neurogenesis and synaptic plasticity. This can translate into more “efficient cerebral perfusion and metabolism, neural and vascular adaptation that contribute to the maintenance of cognitive function” (Lucas, Cotter, Brassard, & Bailey, 2015). Exercise affects all the factors and interactions involved in the regulation of cerebrovascular health, such as brain and metabolic neuronal activity, blood pressure, partial pressure of arterial carbon dioxide, cardiac output and sympathetic nervous activity (Lucas et al., 2015). “The increase in vascular NO bioavailability is considered as a key factor in the maintenance of cerebrovascular function and optimal regulation of CBF (cerebral blood flow)” (Lucas et al., 2015). Exercise can help memory and thinking both directly and indirectly. For example, according to Herting et. al (2016), higher-fit children show better performance on tasks of executive functions, such as attention, compared to low-fit children (Herting, Keenan, & Nagel, 2016) The benefits of exercise come from its ability to reduce insulin resistance, reduce inflammation and stimulate the release of growth factors, which can affect the health of brain cells, the growth of new blood vessels in the brain and angiogenesis of new brain cells (Godman, 2014). Indirectly, exercise can improve mood, sleep, reduce stress and anxiety, all contributors of poor brain health which can lead to cognitive impairment. “Many studies have suggested that the parts of the brain that control thinking and memory (the prefrontal cortex and medial temporal cortex) have greater volume in people who exercise versus people who don’t” (Godman, 2014).
Is it more valuable to the brain to do traditional “cardio” work versus resistance training, and why?
According to Nokia, aerobic exercise can enhance adult hippocampal neurogenesis (AHN). “Adult hippocampal neurogenesis (AHN) is a continuous process through which cells proliferate in the subgranular zone of the dentate gyrus, mature into granule cells and, ultimately, become incorporated into hippocampal neuronal networks “ (Nokia et al., 2016). The increase in AHC is considered to be mediated by an upregulation of BDNF and IGF-1. Compared to a sedentary lifestyle, aerobic exercise had the greatest effect on AHN, whereas HIIT has less effect and there was no effect from resistance training (Nokia et al., 2016). However, there are other changes in the brain promoted by exercise, and that includes changes in the hippocampus and also adult neurogenesis in the subventricular zone, as well as the hypothalamus (Nokia et al., 2016). This suggests the neurogenic effects of exercise occur throughout the brain. According to Herting et. al (2016), aerobic exercise also can lead to better cognition and greater gray matter density in regions responsible for cognitive function, leading to greater thickness and volumes in frontal and parietal regions (Herting et al., 2016).
Even though aerobic exercise promotes the most AHN, this does not mean that resistance training is not beneficial for the brain. In fact, a study published in 2012 indicates that resistance training promotes cognitive and functional brain plasticity with people who are already diagnosed with mild cognitive impairment or at risk for dementia. In the 6 month RCT trial by Nagamatsu et. al, six months of twice-weekly resistance training improved selective attention/conflict resolution, associative memory, and regional patterns of functional brain plasticity (Nagamatsu et al., 2012). This provides some evidence that resistance training can benefit multiple areas of in those already at risk for dementia. Aerobic training demonstrated improved selective attention/cognitive resolution in older women with mild cognitive impairment, whereas the resistance training improved associative memory performance, “co-occuring with positive functional changes in hemodynamic activity in regions involved in the memorization of associations” (Nagamatsu et al., 2012).
If you were to design the ultimate brain-based exercise program what would it look like?
An ideal program would consist of both aerobic and resistance exercise in a combinational format. In fact, an article published in 2018 by Northey et al indicates that exercise that is combined with resistance and cardio can boost brain power of people over 50. This study consisted of a large meta-analysis which includes a large number of studies without imposing a limit on publication date or exercise mode. “This study confirms previous suggestions that resistance training may play an important role in improving cognitive function in older adults” (Northey, Cherbuin, Pumpa, Smee, & Rattray, 2018). Although this does not show that resistance training is better than other modes of exercise, it does suggest that this type of training has particularly pronounced effects on these domains of cognitive function. In addition, this review also demonstrated that multicomponent training (cardio and weights combined) can benefit cognitive function in people over age 50. “Our meta-analysis provides positive evidence for the prescription of both aerobic and resistance training (ie, multicomponent training), in accordance with exercise recommendations, for this age group to specifically improve cognitive functions” (Northey et al., 2018). This confirms what I have suspected and seen anecdotally myself in my classes: combinational classes that utilize both cardio and weights seem to be the most effective on all fronts of health, and that includes cognitive health as well.
There are many types of exercise protocols/prescriptions. The one that I use often is called Metabolic Training. It consists of steady state cardio (typically in aerobic or dance format) with some weight training in either Tabata or some type of timed format. I typically use Rest-Based Training (RBT), which has become popular through one of my mentors Jade Teta. His philosophy is to “push till you can’t, rest till you can”. According to Teta (2017):
RBT is a system that makes rest, not work, the primary goal of the workout. It allows participants to take a rest for as long as necessary. Rest actually becomes a tool for increasing intensity, because exercisers can strategically use it to work harder than they could without rest. It also provides a buffer against overexertion, making even high-intensity workouts safe. In RBT, the protocol adapts to the individual rather than forcing the individual to adjust to it.
The ability for the participant to self-regulate gives them autonomy and more likely to develop and maintain innate motivation (Teta, 2017). “When exercisers have control over when to rest and for how long, work volume can increase while safety is maintained” (Teta, 2017). RBT gives the participant full control of their intensity and gives them ownership to the exercise so that “not only work harder but also become more aware of their physiology and more engaged in their programs” (Teta, 2017). I like this, since half the battle I encounter is keeping my clients motivated and committed to their exercise routine. No matter how effective the prescription is, if it is not maintained, benefits are diminished greatly.
I also like to use a format called “Tabata”. In Tabata, we work hard for 20s and rest for 10 seconds, and continue that pattern for a total of 8 rounds. I mix up strength training with cardio training within a Tabata circuit. It comes out to 4 minutes per set. I often superset two different exercises, often times one strength and one cardio, so they are only doing 4 sets instead of 8. The possibilities with Tabata are endless and we have a lot of fun with it! There are other protocols used by trainers as well, but I have found that the higher duration intervals are not perceived as enjoyable as the lower duration. “Protocols with 120s high-intensity intervals are rated as being less enjoyable than protocols with 30s or 60s high-intensity intervals” (Heisz et al., 2016). According to Heiz, this reduced enjoyment of the more strenuous protocols may be related to the individual’s ability to complete the exercise, or their competence. I have found the Tabata to elicit the most favorable feeling of competence with my participants, especially when the intensities were higher. “Alternatively, the accumulated fatigue or physical stress from chronically performing a strenuous exercise may actually increase negative feelings and reduce enjoyment for the exercise over time” (Heisz et al., 2016). I have taught to all different fitness levels. In my morning gym classes, I typically have younger moms and retired folks attending. The class I teach in my neighborhood clubhouse consists of an age group of 50-60, and they also love Tabata and metabolic conditioning. The duration of the exercise never exceeds 30 minutes, although I have even recommended 15-minute metabolic training when time is constrained.
I have to mention that care must be taken to address the individual variation to exercise training. “Although aerobic exercise is, on average, beneficial for health, its effects vary between individuals, presumably as a result of considerable genetic variance” (Nokia et al., 2016). For some, aerobic training provides substantial gain in maximal aerobic capacity (V˙ O2 max) and metabolic health, whereas for others the same amount of training results in little or even negative change. In fact, there are individual differences in the BDNF gene that has been shown to mediate the effect of exercise and brain cognition and how exercise affects brain and behavior (Herting et al., 2016). “The secretion and intracellular trafficking of BDNF is altered by a common functional single nucleotide polymorphism (SNP) within the BDNF gene, known as the val66met” (Herting et al., 2016). In fact, AHN is highest in animals born with a tendency for a higher response to exercise training and that engage in a large amount of voluntary aerobic activity.
Here is a sample weekly workout program for brain health for someone who responds well to the types of training selected (keeping in mind each individual’s prescription will vary based on their genetics):
Sunday-rest and recovery (gentle walk, yoga, tai chi)
Monday- 20-30 minutes Metabolic Training
Tuesday-rest and recovery
Wendesday-20-30 minutes rest and recovery (gentle walk, yoga, tai chi)
Thursday-30-45 minute steady state cardio (optional)
Friday- 15-30 minutes Metabolic Training
Saturday-choose from Metabolic Conditioning or steady state cardio or rest and recovery (based on biofeedback from the training days earlier in the week)
For more information on how IC Healer can help you , Book a Discovery Call today.
Sign up for my FREE GUIDE
References
BMJ (n.d.) Aerobic and Resistance exercise combo can boost brain power of over 50’s. Retrieved (2018, October 8) from https://www.bmj.com/company/newsroom/aerobic-and-resistance-exercise-combo-can-boost-brain-power-of-over-50s/
Boutcher, S. H. (2011). High-intensity intermittent exercise and fat loss. J Obes, 2011, 868305. doi:10.1155/2011/868305
Foster, C., Farland, C. V., Guidotti, F., Harbin, M., Roberts, B., Schuette, J., . . . Porcari, J. P. (2015). The Effects of High Intensity Interval Training vs Steady State Training on Aerobic and Anaerobic Capacity. J Sports Sci Med, 14(4), 747-755.
Herting, M. M., Keenan, M. F., & Nagel, B. J. (2016). Aerobic Fitness Linked to Cortical Brain Development in Adolescent Males: Preliminary Findings Suggest a Possible Role of BDNF Genotype. Front Hum Neurosci, 10, 327. doi:10.3389/fnhum.2016.00327
Lucas, S. J., Cotter, J. D., Brassard, P., & Bailey, D. M. (2015). High-intensity interval exercise and cerebrovascular health: curiosity, cause, and consequence. J Cereb Blood Flow Metab, 35(6), 902-911. doi:10.1038/jcbfm.2015.49
Nagamatsu, L. S., Handy, T. C., Hsu, C. L., Voss, M., & Liu-Ambrose, T. (2012). Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Intern Med, 172(8), 666-668. doi:10.1001/archinternmed.2012.379
Nokia, M. S., Lensu, S., Ahtiainen, J. P., Johansson, P. P., Koch, L. G., Britton, S. L., & Kainulainen, H. (2016). Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained. J Physiol, 594(7), 1855-1873. doi:10.1113/jp271552
Northey, J. M., Cherbuin, N., Pumpa, K. L., Smee, D. J., & Rattray, B. (2018). Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis. Br J Sports Med, 52(3), 154-160. doi:10.1136/bjsports-2016-096587
Teta, J. (2011). Rest-Based Training. Retrieved (2018, October 8) from http://www.ideafit.com/fitness-library/rest-based-training
I am very interested in alternative therapies that can be used either stand alone or in conjunction with conventional therapies like chemotherapy. I found a paper in regards to AHCC that looked promising, but unfortunately has not reached mainstream. Many immune enhancers are natural compounds that have proved to be nontoxic for humans and with great potential for anticancer activity (Yin, Fujii, & Walshe, 2010). ACHH is active hexose correlated compound (AHCC), an extract prepared from mycelia of the basidiomycete mushroom Lentinula edodes. 74% of AHCC is oligosaccharides containing about 20% of the -1, 4-glucan type. It has received special attention in the past few years by its reported benefits. AHCC is commercially used as a nutritional supplement and contains a mixture of polysaccharides, amino acids, and minerals (Yin et al., 2010). Results of this particular study suggest that AHCC can enhance CD4 and CD8 T cell immune responses in healthy persons via increasing production of cytokines IFN-gamma and TNF-alpha from T cells. It has also been found that the effects of AHCC are more evident in hosts with the impaired immune function. The study measured the frequency of IFN-gamma and TNF-a producing CD4 and CD8 T cells in adults over age 50 before and after taking AHCC. The results were pretty interesting. AHCC was provided as 500-mg capsules. Total daily dose was 3 g (3 capsules twice daily). The production of the cytokines was measured at 30 and 60 days after AHCC intake and 30 days after the last dose. Interestingly, the frequency of CD4 T cell subsets producing the cytokines was higher at 30 and 60 days. Even after 30 days of discontinuing the AHCC, the frequency of CD4 T cells producing the combination of IFN-gamma and TNF-a at visit 4 was still higher compared to baseline levels. This implies that the effect of AHCC on CD4 T cells could last for several weeks even after this compound is discontinued (Yin et al., 2010)
Two published peer-reviewed human clinical studies (on 269 and 40 subjects respectively) evaluating advanced liver cancer showed extended survival, lower recurrence and improved quality of life among patients taking AHCC. Several other studies demonstrated the ability of AHCC to significantly increase NK cell activity in immune compromised patients. “Given the abundance of preliminary positive results across different infections, AHCC supplementation demonstrates valuable and clinically-relevant potential as an immune-enhancing compound” (Pescatore, n.d.). Finally, AHCC boasts a strong safety profile supported by a Phase I study conducted at Harvard, a 20-year history of use in Japan, its adoption by over 700 clinics and use by an estimated 70,000 people worldwide (including 20,000 in the U.S.). Thus, there is a strong case to be made for adding AHCC to a daily supplement regimen to support the body’s immune system, not only during the apparent times of increased infectious threat such as the flu season, but also all year long.
How can this help the population with bladder issues?
Theoretically, AHCC should be able to boost your natural immune system to defend you against pathogens that cause UTI’s. Both human and animal studies have pointed to AHCC’s ability to enhance the activity of natural killer cells (“NK cells”). These cells provide a crucial first defense for the body, launching a rapid attack while the other cells of the immune system are still mobilizing. AHCC has been the subject of several studies, which investigated its potential as a countermeasure to various infectious diseases, methicillin-resistant Staphylococcus aureus (MRSA) and several other opportunistic infections (Klebsiella pneumoniae, Candida albicans and Pseudomonas aeruginosa.) Looking at “opportunistic” or hospital-acquired infections, the effects of AHCC supplementation on the resistance to Klebsiella pneumoniae (principally associated with bacterial pneumonia and urinary tract infections) was studied in both infected and stress induced mice. Again, the AHCC-supplemented mice demonstrated increased survival, increased mean time until death, decreased susceptibility to infection and increased bacterial clearance from the blood.
Here is a link for the product on Amazon: https://amzn.to/2uaEVYN
References
Pescatore, F. (n.d.) AHCC a Powerful Aid in Fighting Viruses and Infections
Yin, Z., Fujii, H., & Walshe, T. (2010). Effects of active hexose correlated compound on frequency of CD4+ and CD8+ T cells producing interferon-gamma and/or tumor necrosis factor-alpha in healthy adults. Hum Immunol, 71(12), 1187-1190. doi:10.1016/j.humimm.2010.08.006
Want to try CBD? Click here for the link to order —>https://ichealer.primemybody.com/prod_FOCUS001
The areas I am going to focus on are Inflammation and the Immune System, Leaky Gut and Pain Management.
What is CBD anyway?
Believe it or not, your body produces endocannabinoids. The endocannabinoid receptors (ECS) are the biggest receptors in your body, and they exist in all higher life forms. The ECS has emerged as one of the key regulatory mechanisms in the brain controlling multiple events such as mood, pain perception, learning and memory among others. “It is also thought to provide a neuroprotective role during traumatic brain injury (TBI) and may be part of the brain’s natural compensatory repair mechanism during neurodegeneration.” (Kendall & Yudowski, 2016) We have two main receptors, CBD1 and CBD2. The CBD1 receptors are found primarily in the central nervous system, and CBD2 is found in immune cells. According to Gyires and Zadori, modulating the activity of the endocannabinoid system (ECS), which comprises CB1 and CB2 receptors, the endocannabinoids and their synthetic and metabolizing enzymes, may have therapeutic potential in numerous diseases including obesity/metabolic syndrome, diabetes, neuro- degenerative, inflammatory, cardiovascular and psychiatric disorders, liver and skin diseases, pain, cachexia, cancer, as well as chemotherapy-induced nausea/vomiting. ((Gyires & Zadori, 2016)
CBD1: Central cannabinoid receptors
“TheCB1 receptor is one of the most abundant G protein-coupled receptors (GPCRs) in the CNS and is found in particularly high levels in the neocortex, hippocampus, basal ganglia, cerebellum and brainstem.”(Kendall & Yudowski, 2016). The CBD-1 receptor binds the THC to mediate most of the CNS effects of it. CB1 receptors also act on 2-aracodonalglycerol (2 AG), which is found in breast milk and CNS as well as annandamines (AD) which is considered the “bliss molecule”. CBD1 receptors are restricted to presynaptic sites, which could indicate a possible role in local modulation of gene and protein expression after chronic receptor activation. CB1 receptors are indicated in many disorders that impact the CNS including several neurodegenerative disorders such as Huntington’s disease (HD), multiple sclerosis (MS) and Alzheimer’s disease (AD).” It’s expression is heterogeneous within the nervous system and is mainly responsible for cannabinoid psychoactive properties.”(McCoy, 2016)
CBD2: peripheral cannabinoid receptors
“The CB2 receptor exhibits a more defined pattern of expression in the brain than CB1 receptors, and is found predominantly in cells and tissues of the immune system.”(Kendall & Yudowski, 2016). They too act on 2AG and AD like CB1. However, in the CNS, CB2 receptor expression is associated with inflammation, particularly in the brain. “Unlike CB1 receptor-mediated cell activation, signal transduction through the CB2 receptor lacks psychotropic effect making it an attractive target for immunotherapy.”(McCoy, 2016)
A word about THC:
The cannabis plant contains more than 60 different active synthetic ligands for CBC1/2 with THC being the major psychoactive molecule among them. At the molecular level, THC acts as a partial agonist (promoter) of the CBD1 receptor. However, THC is not really required for the therapeutic mechanisms of CB1/CB2. Therefore in most over-the-counter products, such as Prime My Body CBD oil, the THC is <0.02%. Depending on the chemistry of the product and the bioavailability of the CBD’s, the THC is not required in high levels for the absorption of CBD.
A summary of what CBD does in your body:
Here is a summary of what CBD can do in your body. Keep in mind, exogenous CBD modulates the receptors; it does not attach directly on them or block them. It can pull up your own endogenous cannabinoid production and molecularly, it can modify gene transcription and stabilize neuroinflammation. For example, it can stabilize over-active glutamate receptors and stabilize activated microglia cells in the brain. In essence, CBD changes the way we create things in our brain. Other benefits of CBD include:
- Turning up genes like glutathione and superoxide dismutase
- Antioxidant
- Protein repair
- Turning down genes that are pro-inflammatory
- Lowering brain inflammation
CBD, INFLAMMATION AND IMMUNE SYSTEM
A fundamental characteristic of the immune system is the ability to distinguish friend and foe…..self and non-self-molecules or antigens. Inflammation is the innate immune response against infectious agents, and the inflammatory response promotes initiation of an adaptive immune response by antigen-specific T and B cells. When the immune system encounters a pathogen, innate immune cells recognize the pathogen via Toll-like receptors and other pattern-recognition receptors to trigger an inflammatory response. “Innate immune cells are an important source of endocannabinoids, and these cells synthesize and metabolize endocannabinoids.”(McCoy, 2016)
For many years, one puzzling aspect of innate immunity has been autoimmune conditions, which are due to inflammatory responses in the absence of an infection that contribute to tissue damage. Important innate immune cells express cannabinoid receptors, and cannabinoids influence their immune functions. For example cannabinoid studies involving toll-like receptors have concentrated in bacterial LPS responses via TLR4 as a classic model for inflammation. “For the most part, exogenous and endogenous cannabinoids interfere with proinflammatory cytokine and nitric oxide production by LPS or LPS stimulated monocytes, macrophages, microglia and macrophage cell lines in culture.”(McCoy, 2016) LPS is released from bacteria cells which are implicated in adrenal and HPA axis in individuals who have chronic bacterial infection. CBD oil can increase CB1 and CB2 receptor expression on peripheral blood monocytes, and “exogenous cannabinoids may alter the endocannabinoid system leading to greater suppression of the LPS response.”(McCoy, 2016) All this means is that using exogenous sources of CBD, such as found in CBD oil, can be used therapeutically to modulate inflammation and subsequent endocrine disruption caused by bacteria and modulate the immune system, which can be helpful in treating autoimmune diseases.
GASTROINTESTINAL ACTIONS OF CANNABINOIDS
There is evidence that activation or inhibition of peripheral and central cannabinoid receptors may influence the function of the GI tract. The existence of a functional endocannabinoid in the gut has been established – as CB1 and CB2 receptors are found in colonic tissue (Coutts and Izzo, 2004). The cannabinoid receptors, the endocannabinoids AEA and 2-AG, and proteins responsible for their synthesis and degradation are widely distributed in the GI tract and several data suggest that their expressions are substantially altered during inflammatory processes. (Gyires & Zadori, 2016) According to (DiPatrizio, 2016):
Evidence also suggests that dysregulation of the endocannabinoid system might play a role in intestinal disorders, including inflammatory bowel disease, irritable bowel syndrome, as well as obesity. There is evidence that the dyregulation can be expressed epigenetically. For example, single-nucleotide polymorphisms in genes for constituents of the endocannabinoid system—including fatty acid amide hydrolase (FAAH), the degradative enzyme for the endocannabinoid, anandamide, and cannabinoid type1receptor(CB1R)—are associated with increased colonic transport and irritable bowel syndrome.
In one study done on rats in 2016, it was seen that the released of non-cholinergic excitatory neurotransmitters may be regulated by CB1 receptors. CB1 and CB2 receptors and enzymes in regulating endocannabinoids can be modulated to protect the gastric mucosa against erosions, mucosal lesions and inflammation. “Activation of cannabinoid receptors by exogenous or endogenous ligands has been shown to decrease the formation of different types of experimental gastric ulcers.”(Gyires & Zadori, 2016) Acid secretion that occurs during NSAID-induced mucosal damage can also be inhibited via the CB1 receptors.
Another area that CBD’s are showing activation of the cannabinoid receptors in the gut that can suppress many of the inflammatory bowel related symptoms, such as diarrhea and visceral hypersensitivity. This is showing promise in modulating disease such as Chron’s disease and ulcerative colitis, both which are complex diseases involving altered intestinal flora that can induce mucosal disruption and result in penetration of luminal antigens into the gut wall. (Gyires & Zadori, 2016)
Below are some areas where there is a large body of evidence that cannabinoids exert on the GI Tract.
- Inhibition of inflammation. CBD can have both immunomodulatory and immunosuppressive effects. These effects are primarily mediated by CB2 receptors localized on macrophages and lymphocytes, but some studies underline the importance of CB1 receptors as well. Due to the complex anti-inflammatory action, cannabinoids can efficiently inhibit the development of colitis, as well as reduce the already established inflammation.
- Modulation of intestinal barrier functions-Epithelial damage and breach of the intestinal barrier are important factors in intestinal diseases and “leaky gut”, which allow bacterial products and other antigens to cross the epithelium and enter the lamina propria, resulting in inflammation and tissue damage. Restoration of the barrier function is an important approach in treating individuals with gut-related conditions. Although the data from various in vitro and in vivo studies are mixed, the anti-inflammatory properties of the cannabinoids can indirectly modify their action on intestinal permeability and improve barrier function. Alhamoruni, Larvin, and O’Sullivan (2012) looked specifically at the role cannabinoids had on intestinal permeability. T hey concluded that “locally produced endocannabinoids, acting via CB1 receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation.” Alhamoruni, Larvin, and O’Sullivan’s (2012) study provides the suggestion that THC and/or CBD can/may (depending on your state) have a therapeutic role in healing IP and their research also provided evidence of a prophylactic role.
- Motility and Secretion-Beside their potent anti-inflammatory property and modulatory effect on intestinal epithelial permeability, cannabinoids also inhibit gastrointestinal motility and secretion, which both may alleviate diarrhea, a common clinical manifestation of IBD. They also have been shown to alleviate visceral hypersensitivity and abdominal pain. (Gyires & Zadori, 2016) Preclinical data suggest that cannabinoids may serve as useful tools for alleviating visceral hypersensitivity and relieving abdominal pain in IBD, and this assumption is supported by preliminary clinical studies, in which IBD-patients treated with cannabis reported a statistically significant pain reduction.
- Gut Microbiome-Several studies suggest the possibility of interactions between the endocannabinoid receptors and gut bacteria. Collectively, these studies underscore the ability for CB1R activation to control endothelial barrier integrity and provide novel evidence for interactions between the endocannabinoid system, gut microbiota, and possibly adiposity.
CBD AND CHRONIC PAIN
Chronic pain represents an emerging public health issue of massive proportions, particularly in view of aging populations in industrialized nations (Russo, 2008). Associated facts and figures are alarming: Responses to an ABC News poll in 2005 in the USA indicated that 19% of adults (38 million) have chronic pain. I am sure those numbers are even higher now. According to Russo, clinicians face difficulties managing intractable patients afflicted with cancer-associated pain, neuropathic pain, and central pain states (e.g., pain associated with multiple sclerosis) that are often inadequately treated with available opiates, antidepressants and anticonvulsant drugs. Therefore, the integration of cannabinoid medicines to the pharmacopoeia offers a novel approach to pain management. I wanted to summarize some of my findings on this topic in regards to pain management. When I searched on PubMed, there were many articles on this topic, so clearly there is quite a bit of research being conducted, but I decided to choose two of them that I felt was most appropriate.
Interesting their functions have been termed “relax, eat, sleep, forget, protect” (Russo, 2008). It demonstrates the ability to mediate the suppression of pain and inflammatory processes (Russo, 2008). Interestingly, a deficiency in endocannabinoid has been found in people suffering from conditions such as migraines, fibromyalgia and intestinal conditions such as IBS.
Below are some areas I bulleted that was particularly of interest in regards to ECS and pain management:
- Cannabinoids proved to be 10-fold more potent than morphine in wide dynamic range neurons mediating pain, through widespread action in areas of the thalamus (Russo, 2008).
- The ECS is active peripherally, where CBD1 stimulation reduces pain, inflammation, and hyperalgesia (Russo, 2008).
- Cannabinoid agonists produce many effects beyond those mediated directly on receptors, including anti-inflammatory effects and interactions with various other neurotransmitter systems (Russo, 2008).
- THC can increase serotonin. It affects widespread serotonergic systems, including its ability to decrease 5-hydroxytryptamine (5-HT) release from platelets, increasing its cerebral production and decreasing synaptosomal uptake (Russo, 2008).
- Cannabinoids pre-synaptically inhibit glutamate release. “The glutamatergic system is integral to development and maintenance of neuropathic pain, and is responsible for generating secondary and tertiary hyperalgesia in migraine and fibromyalgia via NMDA mechanisms” (Russo, 2008)
- THC produces 30%–40% reduction in NMDA responses, making THC a neuroprotective antioxidant (Russo, 2008).
- THC has been shown to stimulate beta-endorphin production by interacting with the endorphin/enkephalin system (Russo, 2008).
- Cannabidiol, inhibits glutamate neurotoxicity, and displays antioxidant activity greater than ascorbic acid (vitamin C) or tocopherol (vitamin E) (Russo, 2008).
- CBD is able to inhibit tumor necrosis factor-alpha (TNF-α) , as seen in a rodent model of rheumatoid arthritis (Russo, 2008).
- Cannabinoids suppress inflammatory and neuropathic pain by targeting a3 glycine receptors (Xiong et al., 2012)
- THC has twenty times the anti-inflammatory potency of aspirin and twice that of hydrocortisone. In contrast to all nonsteroidal anti-inflammatory drugs (NSAIDs), demonstrates no cyclo-oxygenase (COX) inhibition at physiological concentrations. “At a time when great concern is accruing in relation to NSAIDs in relation to COX-1 inhibition (gastrointestinal ulcers and bleeding) and COX-2 inhibition (myocardial infarction and cerebrovascular accidents), CBD, like THC, inhibits neither enzyme at pharmacologically relevant doses” (Russo, 2008).
Based on some of these facts from a small source of literature, I think there are opportunities for further research in the use of CBD supplements to determine if it can be used to complement any therapeutic healing protocol. I believe it has really helped me in many ways.
References
Alhamoruni, A., Wright, K., Larvin, M., & O’Sullivan, S. (2012). Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. British Journal of Pharmacology, 165(8), 2598–2610. http://doi.org/10.1111/j.1476-5381.2011.01589.x (Links to an external site.)
Coutts, A. A., & Izzo, A. A. (2004). The gastrointestinal pharmacology of cannabinoids: An update. Current Opinion in Pharmacology, 4(6), 572–579. https://doi.org/10.1016/j.coph.2004.05.007
DiPatrizio, N. V. (2016). Endocannabinoids in the Gut. Cannabis Cannabinoid Res, 1(1), 67-77. doi:10.1089/can.2016.0001
Gyires, K., & Zadori, Z. S. (2016). Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. Curr Neuropharmacol, 14(8), 935-951.
Kendall, D. A., & Yudowski, G. A. (2016). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Front Cell Neurosci, 10, 294. doi:10.3389/fncel.2016.00294
McCoy, K. L. (2016). Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation. Mediators Inflamm, 2016, 5831315. doi:10.1155/2016/5831315
Russo, E. B. (2008). Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag, 4(1), 245-259.
Xiong, W., Cui, T., Cheng, K., Yang, F., Chen, S. R., Willenbring, D., . . . Zhang, L. (2012). Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha3 glycine receptors. J Exp Med, 209(6), 1121-1134. doi:10.1084/jem.20120242
I have been very interested in histamine and histamine intolerance from the time I was first diagnosed with IC and noticed that allergy medications helped me during flare-ups. It is well known that there is an involvement of mast cells and cystitis related pain. “Interstitial cystitis has been found in combination with some allergic or autoimmune disorders and histopathological abnormalities resembling allergic disorders, including mast cell activation, histamine release, and eosinophil infiltration” (Lee, Doggweiler-Wiygul, Kim, Hill, & Yoo, 2006). Clinical studies demonstrate elevated mast cell numbers in the lamina propria of IC bladder biopsies. This may explain why neuromodulatory therapies suggest are partially effective in IC therapies, as “neural-immune interactions play a role in IC pathogenesis” (Rudick, Bryce, Guichelaar, Berry, & Klumpp, 2008). Mast cells contain preformed stores of immune mediators, such as histamine and TNF, and can be activated to release these stores by neurotransmitters such as substance P, a polypeptide thought to be involved in the synaptic transmission of pain and other nerve impulses. It is hypothesized that the activation of bladder related circuits in the CNS initiate substance P by peripheral nerves in the bladder can promote mast cell activation, mediated by substance P (Rudick et al., 2008). The mast cells are thought to induce bladder inflammation by acting on the bladder epithelium (lining). Also, increased levels of urinary histamine metabolites have been detected in IC patients. This is thought to be due to the accumulation of mast cells in the lamina propria.
A role for histamine and histamine receptors in pain responses has been documented in both humans and animal models. “However, histamine can be derived from various cell types, including mast cells, basophils, and histaminergic neurons” (Rudick et al., 2008). More recently, inflammatory cells such as neutrophils and dendritic cells have been shown to produce histamine. In fact, it has been demonstrated in various clinical settings that antihistamine therapy improves IC-related pelvic pain, and the mechanism for this effect is unknown. However, it can be inferred that this is due to histamine activation. Irritable bowel syndrome (IBS) is another chronic condition that resembles IC in the characteristics of pathology. “In IBS, pain is correlated with activated colonic mucosal mast cells in proximity to nerves” (Rudick et al., 2008). In fact in IBS, colonic tissue extracts often reveal elevated histamine. These findings support the idea that mast cell histamine may mediate pain in multiple pelvic pain syndromes (Rudick et al., 2008).
With my clients, we have a test I run by Dunwoody that can test for histamine intolerance. This test will measure histamine levels, DAO (an enzyme that breaks down histamine), and DAO: histamine ratio. Classic symptoms of histamine intolerance include gas, high blood pressure, arrhythmia, nausea, hives, stomach ache, itching, cramps, headache, sneezing, dizziness, congestion, runny nose, shortness of breath, especially after meals containing histamine. Low DAO is also associated with the same symptoms along with inflammation, arthritis and certain neurological conditions such as MS. Low DAO is also associated with leaky gut and poor gut function and immunity. It can also be a trigger for depression and anxiety. Individuals with the inability to break down histamine seem to “react to everything” or seem to improve on anti-histamines. I have to mention that the low histamine diet, combined with DAO enzyme before meals, has been shown to be really helpful in managing IC pain related to mast cells. To really get on the road to healing and run some of the key functional tests, contact me at mandy@naturalhealthachiever.com so I can better guide you!
To learn more about healing form IC naturally, please visit our website: https://ichealer.com If you are looking for self healing, we recently launched our Self Healing IC Course featuring 10 hours of video designed to help you discover your root cause. Once you know your root cause, you can start your healing journey. To find out more information about our exciting new course, please find the information below:
Here is the link to preview the course: https://ichealer.com/online-course/
Here is the Podia Course Page: https://ichealer.podia.com/course
The first module is totally FREE. You have nothing to lose and everything to gain. For more insightful videos on these burning topics, simply subscribe to this page so you can be notified of up to date information.
Join us on Facebook https://www.facebook.com/IC-Healer-103255207780907/
Instagram https://www.instagram.com/ichealerofficial/
Twitter https://twitter.com/ic_healer
References:
Lee, J., Doggweiler-Wiygul, R., Kim, S., Hill, B. D., & Yoo, T. J. (2006). Is interstitial cystitis an allergic disorder?: A case of interstitial cystitis treated successfully with anti-IgE. Int J Urol, 13(5), 631-634. doi:10.1111/j.1442-2042.2006.01373.x
Rudick, C. N., Bryce, P. J., Guichelaar, L. A., Berry, R. E., & Klumpp, D. J. (2008). Mast cell-derived histamine mediates cystitis pain. PLoS ONE, 3(5), e2096. doi:10.1371/journal.pone.0002096
