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).
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)
- The tennis swing
- The 100-meter sprint
- The baseball swing
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
- 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.
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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
- 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.
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 love strawberries! They are high in Vitamin C and just delicious on salads. Sadly, they also can cause pain in many people who have mast cell activation disorder. Read below….
I have recently become very interested in histamine intolerance and mast cells, and strawberries is on the list of foods high in histamine. There is some significant research being done on mast cell activation, autoimmune disease and the immune system. Histamine intolerance is the disequilibrium between accumulated histamine and histamine degradation (Manzotti, Breda, Di Gioacchino, & Burastero, 2016). Histamine degradation is dependent on the primary enzyme, diamine oxidase (DAO). Histamine is a biogenic amine found in foods such as pickles, matured cheese, fermented foods and leftovers. Some foods are histamine liberators and that includes fruits such as pineapples, bananas, citrus fruits, papayas and strawberries. The ingestion of histamine rich foods can provoke a variety of symptoms such as digestive, arrhythmia, flushing, asthma, hypotension, rhinoconjunctivitis, and headaches. Impaired DAO production is often the culprit, which can result in increased enteral histamine uptake and increased plasma histamine concentrations (Manzotti et al., 2016). Interesting the study by Manzotti demonstrated that 71% of patients reported functional bloating after consuming high histamine foods.
The latest research indicates that mast cells that release histamine and other inflammation in the bloodstream are active participants in autoimmune disease related tissue damage. Increased mast cell activity, release of histamine and other inflammatory agents are frequently seen in autoimmune conditions such as MS, RA and many others (Healing Histamine, n.d.). A variety of receptors including those engaged by antibody, complement, pathogens, and intrinsic danger signals are implicated in mast cell activation in disease (Brown & Hatfield, 2012). Mast cells can also recruit other immune cells such as neutrophils, to the sites of autoimmune destruction. “Mast cells can only act as accessory cells to the self-reactive T and/or antibody driven autoimmune responses” (Brown & Hatfield, 2012). This includes mast cells among one of the major contributors to autoimmunity and should definitely be considered.
Autoimmune and allergic diseases share fundamentally important features in that both are the result of “hypersensitive” immune responses directed toward inherently harmless antigens (Brown & Hatfield, 2012). An early progress of autoimmune disease involves the activation and expansion of T and/or antibody producing B cells that wear autoreactive receptors. These autoreactive T or B cells can then enter the bloodstream and migrate to sites of inflamed tissues expressing relevant autoantigens (Brown & Hatfield, 2012). “T cells, through the elaboration of cytotoxic mediators, and antibodies, through complement fixation or their ability to activate resident accessory cells such as macrophages and mast cells via Fc receptor engagement, can play direct roles in tissue destruction at these sites” (Brown & Hatfield, 2012)
In addition to eliciting the above described adaptive immune response, antigens can engage a class of danger- associated receptors on both adaptive and innate immune cells, including mast cells. These receptors include toll-like receptors (TLRs) and Nacht-LRRs (NLRs) (Brown & Hatfield, 2012). Activation of immune cells through TLRs and NLRs induces the expression of multiple inflammatory mediators that can ultimately result in local tissue damage causing the release of normally sequestered tissue antigen (Brown & Hatfield, 2012). Subsequent recognition of these antigens by T or B cells will induce activation and initiate autoimmunity. Alternatively, infection-induced activation of accessory immune cells, including mast cells, macrophages, and neutrophils, can boost inflammation and transform a relatively modest autoreactive response.
There is evidence that other TLRs are expressed on mast cells. For example, activation of mature mast cells through TLR2 results in their production of several pro-inflammatory cytokines critical in autoimmunity including IL-17, IFNγ, TNF, and IL-1β. Mast cells also express multiple IgG Fc receptors. This is significant because IgG autoantibodies are hallmarks of many autoimmune diseases and have been detected in multiple autoimmune diseases.
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Brown, M. A., & Hatfield, J. K. (2012). Mast Cells are Important Modifiers of Autoimmune Disease: With so Much Evidence, Why is There Still Controversy? Front Immunol, 3, 147. doi:10.3389/fimmu.2012.00147
Healing Histamine (n.d.). Histamine Intolerance, Mast Cells & Autoimmunity. Retrieved (2018, May 15) from https://healinghistamine.com/histamine-mast-cells-autoimmune-disorders/
Manzotti, G., Breda, D., Di Gioacchino, M., & Burastero, S. E. (2016). Serum diamine oxidase activity in patients with histamine intolerance. Int J Immunopathol Pharmacol, 29(1), 105-111. doi:10.1177/0394632015617170