Hydroxychloroquine: An Introduction

Hydroxychloroquine is a derivative of chloroquine that has both anti-inflammatory and antimalarial activities. It is also used as an antirheumatic agent (used to treat joint pain) in systemic lupus erythematosus and rheumatoid arthritis.

The exact mechanism of hydroxychloroquine action is unknown. It has been documented that its activity hampers the parasite’s ability to break down hemoglobin, preventing its normal growth and replication.

Studies have also shown that it inhibits the stimulation of toll-like receptor (TLR) 9 family that induces inflammatory responses by activating the innate immune system.

Several in vitro studies have confirmed the effectiveness of hydroxychloroquine on severe acute respiratory syndrome (SARS) virus. Multiple clinical trials are currently being conducted to identify the effect of hydroxychloroquine on COVID-19.

Genetics and Hydroxychloroquine Response

The IL-10 Gene and Hydroxychloroquine Response

The IL-10 gene contains instructions for the production of a cytokine protein, which plays an anti-inflammatory and immunomodulatory role in lymphocytes. A study in mice documented that the cytokine functions as an essential immunoregulatory in the intestinal tract. Genetic variations in this gene may alter the production of IL-10 and influence the susceptibility to autoimmune diseases.

rs1800896 and Hydroxychloroquine Response
The rs1800896 is a single nucleotide polymorphism or an SNP in the IL-10 gene associated with the regulation of IL­10 production.

Studies have shown that rs1800896 is associated with susceptibility to asthma, inflammatory bowel disease, and other chronic infections.

In a case-control study on patients with SLE (Systemic Lupus Erythematosus), people with TT genotype responded better to hydroxychloroquine.

Summary

  1. Hydroxychloroquine is a drug used to treat acute attacks of malaria, systemic lupus erythematosus (a chronic inflammatory condition of the body), and rheumatoid arthritis.
  2. Hydroxychloroquine works by killing the organisms that cause malaria; however, the exact mechanism of action is unknown.
  3. Several studies have confirmed the effectiveness of hydroxychloroquine on severe acute respiratory syndrome (SARS) virus.
  4. Studies have shown that a person's genetic makeup can influence the response to hydroxychloroquine.
  5. IL-10 gene contains the production of a type of cytokine protein with anti-inflammatory effects.
  6. People with certain variants of this gene gave a better response to hydroxychloroquine than others.

Drug Response And COVID-19

Various existing drugs are being explored in clinical trials for their potential against COVID-19, including Hydroxychloroquine, Lopinavir/ Ritonavir, and VPM1002 (recombinant BCG vaccine).
So far, a newly developed antiviral called Remdesivir is the only drug approved worldwide to treat COVID-19 patients.
Certain genetic variations can affect the metabolism, efficacy, and side effects of drugs. Identifying such variants will help healthcare professionals prescribe the right medication to achieve the best possible beneficial outcomes while avoiding adverse effects.

Response to BCG Vaccine

The BCG (Bacille Calmette-Guerin) is a vaccine that uses a live attenuated strain derived from an isolate of Mycobacterium Bovis, which has been used worldwide against tuberculosis. It is known to provide only partial and inconsistent immunity. The discrepancy in immunity levels between individuals may be due to different BCG vaccine strains, prior exposure to environmental mycobacteria, and host genetics.

It is considered a biologic response modifier, a type of immunotherapy that, when administered, increases immunity to build up the body’s resistance against the disease.

A recent study published in The Journal Of Clinical Investigation analyzed the blood of 6,000 healthcare workers in the Cedars-Sinai Health System for evidence of antibodies against SARS-CoV-2 with their medical history. They documented that workers who had received BCG vaccinations in the past (nearly 30% of of the study population) were significantly less likely to test positive for SARS-CoV-2 antibodies in their blood or to report having had infections with coronavirus or coronavirus-associated symptoms over the prior six months than those who had not received BCG. The authors speculated that the BCG-vaccinated individuals might have been less sick and produced fewer antibodies or mounted a more efficient cellular immune response against the virus.

Genetics and BCG Vaccine

Studies have shown the correlation of certain genetic variants in innate immunity genes and BCG-induced immune responses after vaccination.

The TLR1 and Response to BCG Vaccine

The TLR1 gene encodes a protein that belongs to the Toll-like receptor (TLR) family. It plays an essential role in pathogen recognition and activation of innate immunity. They recognize small molecular motifs (pathogen-associated molecular patterns) expressed on infectious agents and mediate the production of cytokines necessary for the development of effective immunity.
Studies have documented that genetic variants in the TLR pathway that regulate cellular function are associated with susceptibility to some infections, including TB.

rs3923647 and BCG Vaccine Response
The rs3923647 is an SNP in the TLR1 gene. The T allele has been associated with a better immune response upon BCG vaccine administration.

Summary

  1. BCG, or bacilli Calmette-Guerin, is a vaccine for tuberculosis (TB) disease. It is used in countries with a high prevalence of TB to prevent childhood tuberculous meningitis.
  2. BCG has been noted to reduce the incidence of respiratory tract infections in children and adults and have antiviral effects
  3. Based on this, research has proposed that BCG vaccination may induce (partial) protection against the susceptibility to and/or severity of SARS-CoV-2 infection.
  4. Studies have shown that a person's genetic makeup can influence the immune response induced by the BCG vaccine.
  5. People carrying certain variants of the TLR1 or Toll-like receptor 1 gene have better immune responses upon BCG vaccination compared to others.

Dexamethasone: An Introduction

Dexamethasone is a corticosteroid medication used for rheumatic disease, skin infections, hypersensitivity reactions, eye infections, ulcerative colitis, and chronic obstructive pulmonary disorder. Dexamethasone is a glucocorticoid. Glucocorticoids act as an anti-inflammatory drug.

The National Health Service in the UK and the National Institutes of Health (NIH) in the US recommend dexamethasone for patients with COVID-19 who need either mechanical ventilation or supplemental oxygen (without ventilation).

In a clinical trial conducted in the UK, treatment with dexamethasone was shown to reduce mortality rates by a third among COVID-19 patients on ventilators.

Genetics and Dexamethasone Response

The F2RL1 and Dexamethasone Response

The F2RL1 (also known as protease-activated receptor 2) gene contains instructions for the production of a receptor that belongs to the G-protein coupled receptor 1 family of proteins. When activated, they stimulate vascular smooth muscle relaxation, dilate blood vessels, increase blood flow, and lower blood pressure. It is also essential for the inflammatory response, as well as innate and adaptive immunity.

rs2243057 and Dexamethasone response
The rs2243057 is a single nucleotide polymorphism or an SNP in the F2RL1 gene. According to a study, dexamethasone-treated patients with A allele carriers were associated with adverse pleiotropic effects, including osteonecrosis and thrombosis as compared to G allele carriers.

Summary

  1. Dexamethasone belongs to a class of drugs known as corticosteroids, used to treat conditions such as arthritis, allergies, immune system disorders, and certain types of cancer.
  2. Dexamethasone has anti-inflammatory and immunosuppressant effects.
  3. Clinical trials reveal that treatment with dexamethasone reduces mortality rates by a third among COVID-19 patients on ventilators.
  4. Studies have shown that a person's genetic makeup can influence the response to dexamethasone.
  5. The F2RL1 gene, also known as protease-activated receptor 2 regulates the inflammatory response, as well as innate and adaptive immunity.
  6. People with certain variants of this gene are at an increased risk for bone death ad thrombosis when administered this drug.

Coronavirus disease 2019 (COVID-19) is a highly contagious, potentially fatal respiratory illness caused by a coronavirus (SARS-CoV). It was first identified in Wuhan, China, in December 2019, and later it rapidly spread across the world. On March 11, 2020, the World Health Organization (WHO) declared COVID-19 as a pandemic disease.

How is COVID-19 Transmitted?

COVID-19 is likely to transmit through:
1. Respiratory droplets when an infected person coughs or sneezes
2. By touching surfaces contaminated by the virus and then touching the eyes, nose, or mouth.
3. From close contact with an infected person.

Signs and Symptoms

The symptoms of COVID-19 can vary in severity - from very mild to severe illness.
In about 80% of affected people, it causes only mild symptoms.
Some common symptoms include:
1. Shortness of breath or breathing difficulties
2. Fever or chills
3. Cough
4. Fatigue
5. Muscle or body aches
6. Headaches
7. Sore throat
8. Loss of taste or smell
9. Congestion or runny nose
10. Nausea or vomiting

These symptoms may appear between two and fourteen days after exposure to the virus. Children have similar but usually milder symptoms than adults. Older adults and people who have severe underlying medical conditions like heart or lung disease or diabetes are at higher risk of more serious complications from COVID-19.

According to the Chinese Center for Disease Control (CCDC), COVID-19 death cases were already suffering from 10.5% cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer.

Role of Genetics in COVID-19

Genes can determine an individual’s susceptibility to infectious diseases such as COVID-19. They also influence the chances of developing complications from these infections.
Some individuals who get infected remain asymptomatic. Some may develop mild symptoms, while others experience severe symptoms that require hospitalization. These inter-individual differences might be influenced by both genetic and non-genetic factors (environmental/lifestyle).

Research studies have documented that the SARS-CoV-2 virus enters the body by interacting with the ACE2 protein present on the outer surface of certain cells. Certain variants of the ACE2 gene may prevent the SARS-CoV-2 virus from entering cells, thus decreasing a person’s vulnerability to the virus. Variants in LZTFL1, ABO, ACE2, HLA, DPP9, OAS3, IFNAR2, TYK2, and other genes have also been correlated with COVID-19 severity.

A recent genome-wide association study of COVID-19 has shown a significant association of COVID-19 severity with a multigene locus at 3p21.31 and the ABO blood group locus at 9q34.2.

The LZTFL1 Gene

The LZTFL1 gene contains instructions to produce a protein that is widely expressed in the cytoplasm (the fluid that fills the cells) and cilia (hair-like projection found on the surface of the cells). It is involved in protein trafficking (transport) to the ciliary membrane. It functions as a tumor suppressor by interacting with E-cadherin and the actin cytoskeleton, thereby regulating the transition of epithelial cells to mesenchymal cells [ECM].

rs11385942 and COVID-19 Severity
The rs11385942 is an indel (insertion-deletion) variation located in the intronic region of the LZTFL1 gene. Studies have shown that the frequency of minor risk allele (A) was higher among patients receiving mechanical ventilation than those receiving supplemental oxygen only. This finding indicates that this risk allele confers a predisposition to the most severe forms of COVID-19.

The ABO Gene

The ABO gene contains instructions to produce an enzyme called glycosyltransferase that transfers specific sugar residues to H substance and is responsible for the formation of antigens in blood group A and B. Certain variants in the ABO gene are associated with an increased risk for certain cancers and cardio-cerebrovascular disease.

Furthermore, recent studies have documented that blood groups may play a key role in determining the susceptibility and severity of COVID-19. According to a study, people with A blood group are associated with an increased risk of acquiring COVID-19, whereas people with O blood group are associated with a lower risk.

rs657152 and COVID-19 Severity
The rs657152 is a C>A polymorphism in the ABO gene, which may influence several biological molecules, including LDL cholesterol, liver-derived alkaline phosphatase, and interleukin-6, thus contributing to the occurrence and development of the disease.

Based on a GWAS that studied COVID-19 severity, the rs657152 risk allele (A) was significantly associated with a higher risk of a severe COVID infection.

rs657152 and COVID-19 Severity
The rs657152 is a C>A polymorphism located in the intronic region of the ABO gene, which may influence several biological molecules, including LDL cholesterol, liver-derived alkaline phosphatase, and interleukin-6, thus contributing to the occurrence and development of the disease.

Based on a GWAS that studied COVID-19 severity, the rs657152 risk allele (A) was significantly associated with a higher risk of a severe COVID infection.

Summary

  1. Coronavirus disease 2019 (COVID-19) is defined as an illness caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  2. COVID-19 can be transmitted through respiratory droplets, touching contaminated surfaces and touching your mouth, and from close contact with the affected person.
  3. Some signs and symptoms of COVID-19 are cough, fatigue, fever, shortness of breath, and loss of smell and taste.
  4. A person's genetic makeup can influence, to an extent, influences the risk of catching COVID-19, as well as the severity of the disease.
  5. The virus enters the body by interacting with the ACE2 protein produced by the ACE2 gene.
  6. In some individuals, the ACE2 gene produces a higher number of ACE2 proteins and increases both the risk and severity of COVID-19.
  7. Other genes like ABO, LZTFL1, and HLA have also been correlated with COVID-19 severity.

Gut Microbium: An Introduction

The human body’s largest microorganism population resides in the intestine and is collectively called the gut microbiota/microbiome. Every individual’s microbiome is unique and is influenced by genetic, environmental, or lifestyle factors.

The gut microbiome contains a complex community of microbes that live within the gastrointestinal (GI) tract, and many of these microbes are found to be beneficial to health. Some of them, however, can be harmful and promote infections and diseases. It plays an essential role in human health and influences the development of chronic diseases ranging from metabolic disease to colorectal cancer. There is extensive research investigating the biological functions of the gut microbiota in influencing lung disorders that include asthma, chronic obstructive pulmonary disease, chronic bronchitis, lung cancer, pleural effusion, and viral infection. It is also recognized that viral infections in the respiratory tract cause a disturbance in the gut microbiome.

Importance of Bifidobacterium

Some Bifidobacterium strains are considered essential probiotics and are used in the food industry. Different strains of bifidobacteria may exert a range of beneficial health effects, including the regulation of intestinal microbial homeostasis, inhibition of pathogens and harmful bacteria that colonize in the gut mucosa, and regulation of immune responses. It also improves the gut mucosal barrier and lowers levels of endotoxin in the intestine.

Genetics and Bifidobacterium Growth

The MCM6 Gene and Bifidobacterium Growth

The MCM6 gene contains instructions for the production of the protein minichromosome maintenance complex component (MCM). They are essential for the initiation of eukaryotic genome replication. It contains two of the regulatory regions for the LCT gene. This gene produces the lactase enzymes that are required for the digestion of lactose in milk.

Variants in these genes are often associated with lactose intolerance in adult life. The variants result in a decreased ability of the epithelial cells in the small intestine to digest lactose due to the decline in the lactase enzyme.

Research studies have shown the association between _LCT/MCM6_ variants and the abundance of bifidobacterium in the gastrointestinal tract.

rs4988235 and Tendency of Bifidobacterium growth
The rs4988235 is a single nucleotide polymorphism or an SNP in the MCM6 gene. Individuals carrying the homozygous CC variation have been found to be lactose intolerant/ lactose non-persistent, compared to those with the TT or TC variant, which have been correlated with lactase persistence.

Multiple studies have found that rs4988235 has been associated with Bifidobacterium abundance in the gut. As bifidobacterium assimilates lactose as a preferred carbon source for growth, it is reasonable that subjects with the CC genotype have a higher Bifidobacterium abundance in their gut.

The rs4988235 SNP is mainly documented as an essential locus related to lactase activity in the European population.

Summary

  1. Gut microbiota is the microorganisms, including bacteria, archaea, and fungi, in the digestive tracts of humans and other animals, including insects.
  2. The microbiome makeup of each individual is influenced by various factors like genetics, environment, and lifestyle.
  3. Gut microbiota plays an essential role in human health and influences the risk of various chronic diseases.
  4. Viral infections in the respiratory tract cause a disturbance in the gut microbiome.
  5. MCM6 and LCT are two genes that have been studied to influence the abundance of bifidobacterium in the gastrointestinal tract.
  6. People with certain variants in these genes have more bifidobacterium and hence, increases protection against various lung disorders.

Lopinavir and Ritonavir: An Introduction

Lopinavir and Ritonavir are a combination of antiviral medicines used to treat human immunodeficiency virus (HIV) infection. They belong to a class of medications called protease inhibitors, which functions by decreasing the amount of HIV in the blood. When taken together, ritonavir also helps increase the amount of lopinavir in the body. The lopinavir blocks the protease action and results in the formation of defective viruses that cannot infect the body’s cells. As a result, the number of viruses in the body decreases. Nevertheless, it does not prevent the transmission of HIV among individuals, and it does not cure HIV infections.

Preliminary in-vitro studies have shown that the lopinavir/ritonavir combination may inhibit the replication of the Novel Coronavirus. Certain case reports published by scientists from China, Thailand, and Japan have described the effectiveness of this combination in COVID-19. Several clinical trials are currently being conducted to identify the effectiveness, with some showing no benefit and others, some promise.

Genetics and Lopinavir - Ritonavir Response

The CYP3A4 and Lopinavir - Ritonavir Response

The CYP3A4 gene contains instructions for the production of a protein that belongs to the cytochrome P450 superfamily of enzymes. Its expression is induced by glucocorticoids and some pharmacological agents. It catalyzes many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids.

rs28371759 and Lopinavir - Ritonavir Response
The rs28371759 is a single nucleotide polymorphism or an SNP in the CYP3A4 gene. Studies have shown that the minor allele - C is associated with increased enzyme activity, thus facilitating the metabolism of drugs like lopinavir. The minor allele carriers may need to increase the dosage of these drugs compared to wild-type carriers.

Summary

  1. The combination of lopinavir and ritonavir is used with other medications to treat human immunodeficiency virus (HIV) infection.
  2. They belong to a class of medications called protease inhibitors. They work by decreasing the amount of HIV in the blood.
  3. Lopinavir is also an inhibitor of the severe acute respiratory syndrome coronavirus (SARS-CoV)
  4. Studies have shown that a person's genetic makeup can influence the response to lopinavir and ritonavir.
  5. The CYP3A4 gene contains instructions for the production of a protein that belongs to the cytochrome P450 superfamily of enzymes.
  6. CYP450 enzymes are the most prevalent drug-metabolizing enzyme
  7. People with certain variants of the CYP3A4 gene require an increased dosage of lopinavir and ritonavir to achieve the desired effects.

What is Glucose Response?

Glucose response or glucose tolerance is a measure of how fast your body can push glucose from the blood into the muscles and tissues. It is the ability to move glucose load.

Your glucose tolerance can be determined by a glucose tolerance test, which is also used for diabetes diagnosis. The glucose tolerance test helps identify any abnormalities in how your body responds to glucose after a meal.
How’s the test done?

In a healthy individual, a spike in glucose is seen within the first 15 minutes of glucose ingestion. The levels reach the peak at about 30 minutes after ingestion. After 30 minutes, a progressive decline is observed - the 2-hour value should ideally be 25% more than the fasting value - measurement of blood sugar levels after an eight-hour fast. A fasting value of less than 100 mg/dL is considered normal. At 3 hours, the glucose levels should reach the baseline. However, for people with impaired glucose tolerance, the 2-hour value is much higher than the fasting value. For people with diabetes, the glucose value continues to rise till the 2-hour study period.

How Does Exercise Influence Glucose Response?

Exercising contributes to blood sugar maintenance by increasing insulin sensitivity. If your body is sensitive to insulin, it means that it can transport glucose from your blood into the cells to be used as an energy source. Exercising promotes glucose uptake by the muscles. This helps lower blood sugar levels. According to a study, a single bout of exercise can increase insulin sensitivity for at least 16 hours post-exercise.

How Does Genetics Influence Glucose Response To Exercise?

Genes modify the effects of regular physical activity on glucose homeostasis - the maintenance of balance of insulin and glucagon to keep blood sugar levels in check. People with certain changes in genes involved in blood sugar regulation, may have a lesser insulin response than others.

The PPARG Gene

The PPARG gene contains instructions for the production of a protein called peroxisome proliferator-activated receptor-gamma. It plays a critical role in regulating insulin sensitivity and glucose homeostasis and can be associated with improved insulin sensitivity.
Additionally, PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. This gene regulates the functions of other genes as well.

A loss-of-function mutation in the PPARG gene has been associated with insulin resistance, increased blood sugar levels, and increased risk of obesity. Loss-of-function mutations refer to changes in genes that result in reduced or complete loss of gene and protein function.

rs1801282

rs1801282, also known as Pro12Ala, is a single nucleotide polymorphism, or SNP in the PPARG gene. This SNP has been studied to modulate the glucose response upon endurance training. According to a study, the Ala carriers, or G allele carriers (people having GG type) experienced better improvements in glucose and insulin metabolism in response to endurance training.

The IL6 Gene

White blood cells express cytokines. Cytokines are a group of proteins that are expressed by the immune system. They play an important role in cell communication, especially during immune responses.

Some of these cytokines are termed interleukins - abbreviated as IL. IL6 or interleukin 6 is a cytokine that is produced at the site of inflammation. The IL6 gene contains instructions for the production of IL6 protein. Studies suggest that people who are susceptible to type 2 diabetes display features of low-grade inflammation years before the disease sets in.

The IL6 gene, other than its role in immune regulation, also influences glucose homeostasis and metabolism.

rs1800795

rs1800795 is an SNP in the IL6 gene. This SNP has been associated with the circulating levels of the IL6 cytokine. Studies have shown that the C allele of this SNP plays a role in decreased production of IL6 when compared to the G allele.

According to a study, there are differences in training-induced changes amongst the CC, CG, and GG types. The G allele was found to play a role in significantly decreasing the glucose concentration when compared to the C allele.

The LEPR Gene

The LEPR gene contains instructions for the production of a protein called the leptin receptor. The leptin receptor is turned on (activated) by a hormone called leptin. Leptin is released by fat cells. This hormone plays a role in regulating the satiety response in the body. A positive association has been recorded between the size of the fat cells in your body and the amount of leptin hormone - that is, the larger the fat cells, the more the leptin hormone levels.

Leptin has also been associated with glucose homeostasis. It regulates blood sugar levels either by direct or indirect action. Leptin can directly act on peripheral tissues like adipocyte (fat) tissues and muscle tissues or indirectly on the central nervous system.

  1. Leptin stimulates glucose uptake in muscle and brown adipose tissues (brown fat; white fat and brown fat are the two types of fat/adipose tissues found in the body).
  2. It inhibits the release of insulin and glucagon from β cells and α cells, respectively.
  3. It inhibits the release of corticosterone hormone from the adrenal glands - corticosterone stimulates glucose release under stressful conditions. This provides the body with the energy required to ride through the stressful period.
  4. It increases lipolysis (burning of fat) in white adipose tissue (white fat).
  5. There is an overall reduction in glucose output from the liver.

Even in the absence of insulin, leptin can regulate blood sugar levels.

rs1137100

rs1137100 is an SNP in the LEPR gene. This SNP has been associated with glucose tolerance and insulin response. It is also called K109R polymorphism. According to a study, K109R modulates exercise-induced changes in various measures of glucose homeostasis. The study revealed that 109R allele carriers or the G allele carriers had a better glucose response to physical activity when compared to K109 allele carriers or A allele carriers.

Other Factors That Influence Glucose Response

The Effects of Macros on Blood Sugar Levels

Out of the three macros - carbs, proteins, and fats - carbs have the most effect on blood sugar levels. The spike in blood glucose depends on the type of carbs (simple or complex) and the glycemic index (GI) of the food. GI is the measure of how much specific foods increase blood sugar levels.

The effect of fatty foods is seen more profoundly in people with diabetes. They tend to experience a higher insulin resistance upon fatty food consumption. That is, they may require more insulin to regulate their blood sugar levels.

When there’s adequate insulin, protein has very less effect on the sugar levels. However, when there’s an insulin deficiency, protein contributes to an elevation in blood glucose levels.

The Effects of Caffeine and Alcohol on Blood Glucose

In people with diabetes, consumption of caffeine leads to disruption in glucose metabolism. However, in healthy individuals, it has been known to increase insulin sensitivity; therefore, it lowers the risk of type 2 diabetes.

Alcohol can either increase or decrease your blood sugar levels, depending on how much you drink. The liver plays a role in glucose homeostasis by releasing glucose when the levels are lower in the body. When alcohol is consumed, the liver gets busy with breaking down the alcohol. This can lead to low blood sugar levels.

The Dawn Phenomenon

The dawn phenomenon refers to the natural increase in blood sugar levels that occurs early in the morning. This is due to the changes in the hormonal levels in the body. It occurs both in people with and without diabetes. In healthy people, the insulin release is triggered, which brings the blood sugar levels back to normal. However, in case of diabetes, this doesn’t happen. As a result, those with diabetes may experience certain symptoms associated with elevated blood sugar levels.

Insufficient Sleep and Blood Glucose Levels

Even partial sleep deprivation can contribute to insulin resistance. This, in turn, can increase blood sugar levels.

Menstrual Cycle and Blood Glucose Levels

The different stages of the cycle impact your glucose levels in different ways. This effect can vary from woman to woman and even from month to month! While some women have reported an increase in blood sugar levels during their periods, others report a sharp decline in sugar levels! A few days before, after, and during your periods, the levels of estrogen and progesterone change. This can induce temporary resistance to insulin which can last for up to a few days and then drop off.

Exercise Recommendations For Increasing Glucose Tolerance

While any regular physical activity can help control blood sugar levels, certain exercise tips can help magnify the effects on blood sugar levels.

1. Brisk walking

Walking is probably one of the most prescribed activities for people with type 2 diabetes. Brisk walking, done at a pace that raises the heart rate, is considered a moderate-intensity exercise. Moderate-intensity exercises make your heart beat a little faster. This encourages your muscles to use more glucose.

2. Exercising after eating

According to a study, glucose levels hit the peak 60-90 mins after meals. So it is a good idea to begin your workout 30 mins post eating.

3. Yoga

When stress levels are high, cortisol hormone is released, which increases blood sugar levels. So, by managing stress, you can also keep your blood sugar levels in check. What better way to manage stress than yoga? According to a review study, yoga can help control stress and manage diabetes.

4. Checking your blood sugar levels

It is important to monitor your blood sugar levels both before and after exercise just to see how your body responds to exercise.

5. Resistance and aerobic training

Both these forms of training have proven to effectively reduce insulin resistance in previously sedentary older adults with abdominal obesity at risk for diabetes. However, combining both these exercises has been studied to be more effective than doing either one alone.

Summary

  1. Glucose response is a term used to describe how our body handles glucose - how fast glucose enters the cells and muscles, and the insulin response to glucose. Your glucose response can be measured by a test called glucose tolerance test or GTT.
  2. Insulin and glucagon are two hormones secreted by the pancreas. Insulin lowers the blood sugar levels by pushing them into the cells, and glucagon raises the levels by releasing stored glucose from the liver.
  3. Exercises help maintain blood sugar levels by promoting insulin sensitivity. After exercising, the muscles take up more glucose from the blood, thereby reducing your blood sugar levels.
  4. Certain genes influence the glucose response to exercise. One such gene is the LEPR gene, which has been associated with glucose homeostasis; people with the G allele of an SNP in LEPR experience a better glucose response to physical activities.
  5. Other than physical activities, a lot of factors influence your glucose response. They include macronutrient consumption, caffeine and alcohol habits, sleep habits, and the stage of the menstrual cycle.

References

https://pubmed.ncbi.nlm.nih.gov/10683091/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840709/
https://diabetes.diabetesjournals.org/content/54/suppl_2/S114
https://www.snpedia.com/index.php/Rs1800795
https://pubmed.ncbi.nlm.nih.gov/15180970/
https://pubmed.ncbi.nlm.nih.gov/15161768/
https://pubmed.ncbi.nlm.nih.gov/9416027/
https://pubmed.ncbi.nlm.nih.gov/14706966/
https://www.frontiersin.org/articles/10.3389/fendo.2017.00228/full
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145966/

What Is Pain Tolerance?

Pain is defined as an uncomfortable feeling in response to intense or damaging stimuli. An external stimulus like the pricking of skin, heat, or pressure is detected by the pain receptors. The pain receptors activate the nerve fibers nearby. The nerve fibers send signals through the spinal cord to the brainstem. From here, the signals are sent to the brain. This signal is interpreted as pain, and the brain sets off reflexes that can help stop or deal with the pain.

Pain can be a good thing. Pain alerts your brain and tells you that something is wrong. There is a potential illness or injury that needs to be taken care of.

The maximum amount of pain you can handle is termed pain tolerance. This is different from the pain threshold, which is the minimum point at which a stimulus like pressure or heat causes pain.

Pain can be acute or chronic. It can occur due to a specific injury or overall body aches. The level of pain you can tolerate depends on several biological and psychological factors. Pain tolerance or sensitivity varies from person to person.

Exercise and Pain Tolerance

Regular exercise has many benefits. It keeps you healthy, fit, and reduces pain. Research shows that exercise can help increase your pain tolerance also.

A study was done in 2014 to examine the effect of aerobic exercise training on pain sensitivity in healthy individuals. The results of the study show that moderate to high-intensity aerobic training increases ischemic pain tolerance in healthy individuals. The study focussed on ischemic pain, the burning pain you feel when your muscles don’t get enough oxygen, and pressure pain, the pain you feel when excess pressure is applied to a muscle. Other studies show that exercise increases pressure pain tolerance also.

Exercise is shown to increase pain tolerance in people who suffer from chronic pain and post-traumatic stress disorder(PTSD).

How Does Genetics Influence Pain Sensitivity?

Several genes that affect the way you perceive different kinds of pain have been identified. Apart from other factors, your genes also influence how you respond to pain.

COMT Gene

The COMT gene encodes an enzyme called catechol-O-methyltransferase. This enzyme breaks down catecholamines, fight or flight hormones. This gene influences the development of our personalities, identities, and dispositions. Variations in this gene are associated with stress, pain, and anxiety.

rs4680
The GG genotype of this SNP is associated with higher pain tolerance compared to the AA genotype. The AG genotype is associated with intermediate pain tolerance.

Non-Genetic Factors That Affect Pain Sensitivity

Age: Pain tolerance increases with age; as you experience more pain, your body gets used to it.

Gender: Studies report that females are more sensitive to pain.

Stress: Stress can decrease your pain tolerance and make the pain feel more severe.

Chronic illness People with chronic illnesses like migraines tend to become more sensitive to pain.

Mental illness: People with depression or anxiety disorders have lesser pain tolerance.

Past experiences: Your past experiences influence how you perceive pain. For example, if you live in a cold climate for a very long time, you get used to the temperature conditions. This makes you less sensitive to extreme temperatures and increases your pain tolerance.

Expectations: This is a psychological thing. A person who expects more pain tends to feel more intense pain. Your coping strategies and thinking affect how you react to painful experiences.

How To Increase Your Pain Tolerance?

Exercise: Research shows that exercise is an effective way of increasing pain tolerance or decreasing pain sensitivity. Physical activities, especially aerobic exercises like cycling, can increase your pain tolerance. Pain tolerance increases as you work out consistently for longer periods of time.

Yoga: Studies show that people who regularly practice yoga have a higher pain tolerance. Yoga helps you relax, reduce stress, deal with depression and anxiety, and makes you more aware of your mind and body.

Vocalization: Vocalizing your feelings when you experience pain can help you tolerate it for longer. Studies show that people who say a simple ‘ow’ or curse while experiencing painfully cold water can withstand the pain for much longer. People who cursed seemed to have greater pain tolerance.

Biofeedback: This is a type of therapy that makes a person more aware of their body or mind and the response to stimuli like pain. The therapist will teach you techniques to control your response to pain. Mental imaging, breathing exercises, relaxation techniques are some of the methods used in this therapy.

Summary

  1. Pain is an uncomfortable feeling in response to intense or damaging stimuli. It alerts your brain and tells you that something is wrong.
  2. The maximum amount of pain you can handle is termed pain tolerance. This varies from person to person and is influenced by several biological and psychological factors.
  3. People with the GG genotype of SNP rs4680 found in the COMT gene have higher pain tolerance compared to people with the AA genotype. People with the AG genotype are found to have intermediate pain tolerance.
  4. Age, gender, stress, mental illnesses, chronic conditions, past experiences, and expectations influence the way you perceive pain and pain tolerance.
  5. Exercise, yoga, biofeedback therapy, and vocalizing your feelings can help you increase your pain tolerance.

References

https://www.healthline.com/health/high-pain-tolerance#factors
https://www.webmd.com/pain-management/features/whats-your-pain-tolerance
https://www.medicalnewstoday.com/articles/high-pain-tolerance#causes
https://well.blogs.nytimes.com/2014/08/13/how-exercise-helps-us-tolerate-pain/
https://pubmed.ncbi.nlm.nih.gov/24504426/
https://pubmed.ncbi.nlm.nih.gov/12595695/

What Is Blood Pressure?

When blood flows through your arteries, the force that it exerts against the wall of the arteries is measured as blood pressure. It can also be understood as the resistance offered by the blood vessels to the flow of blood. Blood pressure also takes into account the amount of blood that flows through your vessels. It is calculated by multiplying cardiac output and total peripheral resistance, which is the resistance provided by the walls of blood vessels.

Normal blood pressure readings are usually around 120/80 mmHg.

Blood pressure can fluctuate in response to changes in diet, physical activity, body size, health, and diseases that affect the blood vessels.

During exercise or high-stress situations, the heart rate increases, which leads to an increase in cardiac output. This leads to a rise in blood pressure.

Blood Pressure and Exercise

After a workout, your blood pressure normally rises due to an increase in physical activity and heart rate. It should return to its resting level in some time. The sooner it returns to its resting level, the more healthy you are.

When you exercise, your muscles need more oxygen, and hence, the demand for blood increases. To supply more blood to the muscles, the heart has to beat faster and pump a large volume of blood into the vessels. This large volume of blood being pumped increases the blood pressure.

Exercise increases your systolic blood pressure levels. This is a measure of blood pressure when your heart is beating. Diastolic reading is a measure of blood pressure when your heart is at rest in between heartbeats. This is not greatly affected by exercise.

During cycling, working out, swimming, or running, your muscles need more oxygen, and this increases the demand on the heart. Your heart starts pumping faster and harder, and this leads to an increase in systolic pressure.

The blood pressure readings after exercise vary from person to person.

After exercise, your systolic pressure can increase to a value between 160 mmHg and 220 mmHg. Beyond this is a cause for concern, and you need to talk to your doctor. It might be exercise hypertension, which is an extreme spike in blood pressure due to exercise.

Heavy resistance training that includes weight lifting can cause a greater increase in blood pressure compared to aerobic training. This is because of the increase in intra-abdominal pressure and compressive forces exerted by the equipment.

High blood pressure on exercising is usually a rise in pressure more than 140/90 mmHg after two hours of rest. Low blood pressure readings are anything below 90/60 mmHg after two hours of rest on exercising.

Exercise can also be an effective way of lowering blood pressure in hypertensive people. With age, you tend to get blood pressure related problems, but these can be controlled with the right medication and exercise. As you keep exercising, your heart works harder and becomes stronger. Your heart can pump more blood without exerting extra force on your arteries and this can bring your blood pressure levels back to normal. People with hypertension are not usually recommended to do heavy resistance training as this may lead to high spikes in blood pressure. Talk to your doctor about your exercise plan if you’re hypertensive.

How Does Genetics Influence Blood Pressure Response to Exercise?

GNAS Gene

The GNAS gene encodes a protein part of the G protein complex. G protein complexes are involved in many cell signaling pathways. It is involved in the changes of calcium and potassium ion concentrations within cells. These changes are important in regulating cardiac output and peripheral vascular resistance, which is used to calculate blood pressure. Variants of this gene are studied in relation to hypertension.

rs62205366
rs62205366 is an SNP in the GNAS gene. According to a study conducted, men with the T allele and a family history of hypertension had lower blood pressure after performing low-intensity aerobic exercise compared to those with the CC genotype.

Non-genetic Factors That Affect Blood Pressure Response to Exercise

Physical activity and fitness: Exercising consistently and remaining fit helps your blood pressure drop back to its resting state after exercise. This is because as you exercise, you strengthen your cardiovascular system.

Heart rate: Blood pressure recovery is faster in people with lower resting heart rates. Lower resting heart rate is also associated with good health and a lesser risk of cardiovascular disease mortality.

Smoking: Smoking increases blood pressure and heart rate. It is also found to increase blood pressure recovery times after exercise.

Age: In older people, blood pressure spikes after exercise take a longer time to decrease than in younger people.

Obesity: Obesity is linked to a risk of cardiovascular diseases. People who are overweight or obese tend to take longer to recover from blood pressure spikes after exercise.

What Can You Do To Manage Blood Pressure?

An overall fitness plan targeted to your body type is an effective way to control blood pressure. Aerobic exercises are very effective at controlling high blood pressure. Aerobic exercises increase your heart and breathing rate gradually, and this makes your heart stronger, in the long run, reducing blood pressure. Aerobic exercises include running or jogging, jump rope, and exercising on the elliptical machine.

Increase the intensity of exercise gradually. If you feel any trouble like shortness of breath, an irregular heartbeat, or dizziness, stop immediately and consult a doctor.

Weight training can have long-term benefits in controlling blood pressure. Hypertensive people are usually asked to avoid lifting weights, as it causes a high increase in blood pressure. Weight training is a high-intensity workout and can lead to major spikes in blood pressure. This is a temporary risk. If done correctly, weight training can be beneficial in the long run.
While including weight training in your regular exercise plan,
- Use proper form and technique to minimize injury.
- Breathe easily and consistently, don’t hold your breath
- Don’t strain yourself too much. Stop the activity if you feel any unbearable pressure or pain.
- Lifting heavier weights might be more strenuous. Instead, opt for lighter weights and increase the number of repetitions.

Before adding weight training to your exercise plan, if you’re hypertensive, talk to your doctor to come up with a suitable plan that can help you.

Summary

  1. Blood pressure spikes during exercise because the blood supply-demand on the heart increases. Your muscles need more oxygen supply during exercise. The heart starts pumping faster, and this leads to a rise in systolic pressure.
  2. The sooner the blood pressure spike drops after exercise, the more fit and healthy you are. Some people have exercise hypertension, which is a constant high spike in blood pressure, and this is a cause for concern.
  3. Variations in the EDN1 and GNAS genes are associated with differences in blood pressure. Men with a history of hypertension, having the T allele of SNP rs62205366 found in the GNAS gene, were found to have lower blood pressure after aerobic activity. The G allele of SNP rs5370 found in the EDN1 gene puts people at a higher risk of hypertension.
  4. Fitness, physical activity, smoking, age, obesity, and heart rate influence blood pressure recovery times after exercise.
  5. Exercise can also be an effective way to control blood pressure in hypertensive people. Aerobic exercises can help lower blood pressure. Weight training, if done properly, can be effective in the long run.

References

https://www.healthline.com/health/blood-pressure-after-exercise#effects
https://www.health.harvard.edu/heart-health/are-my-blood-pressure-and-heart-rate-changing-normally-during-exercise
https://www.verywellhealth.com/should-my-blood-pressure-be-12080-even-after-exercise-1764088
https://pubmed.ncbi.nlm.nih.gov/17938376/
https://benthamopen.com/contents/pdf/VDP/VDP-6-56.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738943/

What Are Triglycerides?

Triglycerides are types of fat that are commonly found in the human body. The name ‘triglyceride’ means a combination of three kinds of fats combined with a form of glucose called glycerol. The three kinds of fats are - unsaturated fats, saturated fats, and a combination of both.

Triglycerides are majorly present in the fat deposits in the body. These are also present in the blood. These hold on to unused calories in the body and reserve them for future use.

Sources of Triglycerides

There are two ways your body receives triglycerides.

Most of the foods we eat are sources of triglycerides. Excess fat in food directly gets stored as triglycerides, while excess carbohydrates and sugars are converted to triglycerides by the liver and stored.

Triglyceride Levels and Exercise

Your triglyceride levels increase when you consume more calories than what your body can burn. When you exercise, you burn extra calories and hence prevent the increase in triglyceride levels.

A 1982 study analyzed the levels of triglycerides in endurance athletes after long sessions of working out. The study concluded that there was a significant decrease in serum triglyceride levels after 1-hour and 2-hour sessions of exercise.

Another study considered the effects of aerobic exercise on serum triglyceride concentration levels. The study included 38 patients with existing Coronary Heart Disease (CHD). One group underwent aerobic training for eight weeks, and the other group remained sedentary.

The study concluded that people who exercised showed a lowered concentration of triglyceride levels.

A large-scale 2014 study analyzed the results of 13 independent studies relating aerobic exercise, resistance training, and combined exercise on triglyceride levels. According to the study:

Importance Of Triglycerides

Triglycerides are major energy sources in the body. Every unit of triglyceride contains more energy than one unit of protein or carbohydrates. That is why you feel full and sated when you eat a fat-based meal.

When you consume triglycerides, they reach the intestine. Here, they are combined with particles called lipoproteins. Lipoproteins transport lipid (fat) molecules through the plasma to other parts of the body.

Lipoproteins take the triglyceride particles to different muscles and tissues that need energy.

Triglycerides are stored in the fat tissues and the liver in the body. If you are suddenly deprived of food and are starving, stored triglycerides are broken down in the fat tissues and are used for energy. Triglycerides are hence very important backup energy sources.

According to the National Cholesterol Education Program (NCED), here are the different categories based on recommended triglyceride levels.

Genetics And Its Influence On Exercise-induced Changes In Triglyceride Levels

Familial Hypertriglyceridemia - This is an inherited condition where the liver overproduces Very-Low-Density Lipoproteins (VLDL). VLDLs are responsible for carrying triglycerides to the tissues of the body from the liver. High VLDL levels also increase blood triglyceride values.

The CYYR1 Gene

The Cysteine and tyrosine-rich 1 gene (CYYR gene) contains instructions for the production of the CYYR protein. The exact functionality of this protein is not understood yet.

rs222158

The A allele of the SNP rs222158 of this gene affects triglyceride training-response. This allele is associated with decreased triglyceride levels in response to exercise.

The GLT8D2 Gene

The GLT8D2 gene (Glycosyltransferase 8 Domain Containing 2 gene) is responsible for the production of the GLT8D2 protein. This protein plays a role in glycosyl transfer.

rs2722171

The C allele of the SNP rs2722171 of this gene is associated with a decrease in triglyceride levels in response to exercise.

The RBFOX1 Gene

The RBFOX1 gene (RNA Binding Fox-1 Homolog 1 gene) produces the RNA binding protein fox-1 homolog 1. Abnormalities in the protein can lead to neurodegenerative diseases.

rs1906058

The C allele of this SNP is associated with an increase in triglyceride levels in response to exercise

Non-Genetic Influences On Exercise-induced Changes In Triglyceride Levels

The type of exercise - If you want to bring down your triglyceride levels with exercise, choosing the right workout regime is important.
Aerobic exercises are the best choices for lowering triglycerides. You can also try resistance exercises. High-intensity exercises are better as they quickly burn fat and help lower your triglyceride levels.

Excess fat consumption - When you keep consuming excess fatty-foods, even when you exercise rigorously, the body will always have excess fat reserves, and hence the triglyceride values will not decrease.

Excess carbohydrate consumption - People who consume excess carbohydrates and simple sugars are at high risk for developing high levels of triglycerides. This condition is called carbohydrate-induced hypertriglyceridemia.

Studies show that when more than 55% of the energy consumed is through carbohydrates, the body works in converting excess carbohydrates into fat.

As a result, even if you are controlling the amount of fat you consume and are working out, your triglyceride levels will not reduce as much as you expected.

Smoking - A study compared the fasting triglyceride levels in smokers and non-smokers. It concluded that smokers had high fasting triglyceride levels when compared to non-smokers.

Another study analyzed the effects of smoking on aerobic capacity and concluded that the muscles in the bodies of smokers receive less oxygen than in non-smokers, and hence smokers are unable to perform intensive workouts.

Smoking increases triglyceride levels and brings down a person’s ability to exercise effectively. As a result, in smokers, exercising does not cause a considerable reduction in triglyceride levels when compared to non-smokers.

Why Are High Levels Of Triglycerides Problematic?

Triglyceride levels can be identified with a simple blood test. When your blood shows higher levels of triglycerides, here are risk factors to consider:

Recommendations To Improve The Effectiveness Of Exercise In Lowering Triglyceride Levels

Try a combination of exercise and a calorie-restricted diet

The more regularly you work out, the more fat your body will burn. Studies show that when you don’t exercise and go on a calorie-restricted diet, it doesn’t affect triglyceride levels as much as exercise does. A combination of moderate to high-intensity exercise and a calorie-restricted diet plan works wonders.

Change your diet plan

Opt for a high protein and moderate fat and carbohydrate diet. A high-fiber diet is also considered beneficial. Restrict consuming trans and saturated fats. These changes help you exercise better and, as a result, reduce your triglyceride levels.

Slowly build your stamina

Sometimes, existing health conditions, age, and other related factors can prevent a person from taking up exercising. In that case, slowly build up your stamina. Start with low-intensity workouts like walking and then move on to aerobic and resistance training. With time, you will be able to work out enough to lower your triglyceride levels.

Summary

  1. Triglycerides are unsaturated and saturated fats that combine with a kind of glucose in the body called glycerol. Triglycerides are stored in the fat tissues and liver and are also present in blood serum.
  2. Triglycerides act as a reservoir of energy and are burnt when the body is starved.
  3. High levels of triglycerides can be a risk factor for heart conditions, stroke, arteriosclerosis, and non-alcoholic fatty liver disease.
  4. The more you exercise, the more fat stored in the body is burnt. This brings down triglyceride levels.
  5. Certain changes in the CYYR1, RBFOX1, and GLT8D2 genes all determine how exercise influences triglyceride levels in the body.
  6. The type of exercise you take up makes a difference in how quickly your triglyceride levels drop. Aerobic and resistance exercises are considered more effective.
  7. Excess consumption of carbohydrates and sugar and excess fat consumption bring down the effectiveness of exercise in lowering triglyceride levels.
  8. Smoking also hinders the ability of exercise to reduce triglyceride levels. A combination of a calorie-restricted diet and exercise works great in bringing down triglyceride levels.

References

https://en.wikipedia.org/wiki/Triglyceride

https://www.heartuk.org.uk/cholesterol/triglycerides
https://www.uofmhealth.org/health-library/zp3387
https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/triglycerides/art-20048186
https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=56&contentid=2967
https://www.medicinenet.com/how_to_lower_triglycerides_naturally/article.htm

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