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Inflammation and Type 2 Diabetes

Chronic low-grade inflammation is found in type 2 diabetes mellitus (T2DM), and this contributes to the development of T2DM and the associated complications of nerve, kidney, heart, brain, liver, and eye damage.  Interestingly, this inflammation is similar clinically and molecularly to the low-grade inflammation that comes with the ageing process. This process is sometimes referred to as inflammageing. This whole process of inflammation in T2DM is characterised by 4 components: long-term immune system activation, build-up of senescent cells, epigenetic changes, and changes in the intestinal microbiota.

Chronically high BG also leads to increased cellular senescence.  This is basically a state in which the cells are no longer undergoing normal cellular cycles and are not really alive and not really dead.  Consequently they have more DNA damage and seem to spread their senescence to other cells, almost like an infection.  More and more research is associating the accumulation of these cells with chronic and age-related diseases.  Fortunately these senescent cells, like many cancer cells, seem to depend on glucose to keep them alive which makes them susceptible to treatment with an appropriate diet and medical therapy.

A healthy immune system deals with challenges as they arise, increasing in activity when there is a foreign invader, and reducing activity when the challenge has been overcome. The high levels of blood glucose (BG), triglycerides, and “unhealthy” cholesterol found in T2DM lead to an inflammatory response by the immune system.  This process results in immune cells becoming senescent. This is essentially what happens in the  deterioration of the immune system that normally occurs with ageing.  This inflammatory reaction seems to be related to the degree of BG overload, which makes it possible to address by controlling the BG level. This is often done with medications but can also be done sustainably with a proper diet.  Glucose is not the only culprit though, saturated fatty acids (SFAs) produce pro-inflammatory immune responses which lead to insulin resistance as well.

Epigenetic changes are those in which the DNA sequence doesn’t change, but the expression of the genes coded by the DNA does.  DNA methylation is the process that affects the expression of a gene without changing the DNA. This process is influenced by external factors such as the environment, lifestyle, and nutrition. In T2DM the epigenetic changes appear to be mostly pro-inflammatory and the DNA methylation in the pancreas has a negative effect on insulin secretion.  Some of these epigenetic changes remain even after blood sugar levels return to normal, but DNA methylation changes may be reversible with diet, exercise, and weight control.

The connection between diet, the gut bacteria, and inflammation has been garnering more attention in recent years and this may have special relevance for individuals with T2DM.  Over time the balance of the gut bacteria, the microbiota, undergoes changes.  In people who have an imbalance or deficiency of healthy gut bacteria, leakage of bacteria and associated compounds across the gut membrane can occur and lead to chronic low-grade inflammation of the type that is associated with inflammageing. Studies on the microbiota of T2DM patients have found changes in the levels of specific species of bacteria in the gut that contribute to increased inflammation. This balance of gut bacteria can be influenced by factors such as artificial sweeteners, obesity, fiber intake, flavonoids, polyphenols, and supplementation with specific probiotics.

Current medical therapy for diabetes, which consist primarily in oral antihyperglycemic agents such as metformin, does not provide adequate reductions in heart disease and death rates in T2DM patients. Such therapy also does not adequately control the complications of chronically high BG levels.  A more effective and balanced approach should include dietary, lifestyle, and medical interventions that reduce inflammation and address the known mechanisms that result in T2DM and its complications.  Such an approach would rely on a low-carbohydrate or Mediterranean diet, regular strenuous exercise, and nutritional supplementation to mitigate the damaging effects of chronically high BG and the fluctuations in BG that occur when making diet and lifestyle changes.

References:

Prattichizzo F, De Nigris V, Spiga R, Mancuso E, La Sala L, Antonicelli R, Testa R, Procopio AD, Olivieri F, Ceriello A. Inflammageing and metaflammation: The yin and yang of type 2 diabetes. Ageing Res Rev. 2017 Oct 25. pii: S1568-1637(17)30178-2. doi:  0.1016/j.arr.2017.10.003. [Epub ahead of print] Review. PubMed PMID: 29081381.

Khullar M, Cheema BS, Raut SK. Emerging Evidence of Epigenetic Modifications in Vascular Complication of Diabetes. Front Endocrinol (Lausanne). 2017 Sep 29;8:237. doi: 10.3389/fendo.2017.00237. eCollection 2017. Review. PubMed PMID: 29085333; PubMed Central PMCID: PMC5649155.

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Coffee Drinking Reduces Death Risk : EPIC Study

A research article just released in the Annals of Internal Medicine suggests that coffee consumption is associated with a lower risk of death in European countries.  This analysis of data from the EPIC (European Prospective Investigation into Cancer and Nutrition) study included over 450,000 subjects for an average of 16.4 years from 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom).

The study took into consideration several variables that also have an effect on mortality, specifically body mass index, physical activity, smoking status and duration, menopausal status and history of contraceptives and hormone replacement therapy, education, alcohol consumption, total energy intake, consumption of red and processed meats, and fruit and vegetable consumption.

Here are some of the interesting and statistically significant relationships that they found in this study.  These numbers represent the hazard ratios(probability of the outcome in one group divided by the probability of the outcome in the other group) expressed as a percentage for men and women that were in the highest quartile of coffee consumers as compared to non-coffee drinkers.

Cause of mortalityMenWomen
All-Cause88%93%
Digestive Disease41%60%
Circulatory Disease ~78%
Cerebrovascular Disease ~70%
Ovarian Cancer ~131%

The most significant benefit here seems to be the reduction in the risk of death from digestive diseases(ICD 10 codes K00-K93). This category includes ulcerative colitis, crohn’s disease, and several non-infectious types of liver disease, with more than one-third of the observed deaths being due to liver disease.  The authors note that when comparing the highest coffee consumers and non-consumers the reduction in death from liver disease is quite significant but for non-liver diseases the results are inconclusive.  One of the other outcomes that was noted in this and other studies was the improved liver function in coffee drinkers, as determined by measurements of liver enzymes. This might partly explain the reduction in liver disease death risk.

As has also been found in other large studies, increased coffee consumption reduces the risk of all-cause mortality in both men and women.  In this study the association with all-cause mortality was generally apparent for both caffeinated and decaffeinated coffee. The decreased risk of strokes in women consuming coffee, as found here, has also been confirmed in other studies.

One more concerning finding, shown in the table, is the apparent increased risk of death from ovarian cancer in the highest quartile of coffee drinkers.  This is not the first time that an association like this has been found, but other studies have been done that have not shown this relationship. It is something to consider if you have any risk factors for ovarian cancer.

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The Link Between Diet & Depression

There is some very interesting research around the relationship between inflammation and depression.  There is some evidence that inflammation could mediate risk factors for depression, and some randomized trials have found anti-inflammatory agents to be effective in the treatment of major depression.

Several studies have looked at the influence of diet on chronic inflammation.  Foods contain biologically active compounds that have either pro- or anti-inflammatory properties that can be observed by their effects on markers of inflammation in the body.  Research in this area has led to the developments of the Dietary Inflammatory Index (DII). The DII can be used to estimate the effects of diet on a person’s level of inflammation.  Some studies have shown that a higher DII score, corresponding to a pro-inflammatory diet, was linked to a higher risk of cardiovascular disease, poorer cognitive functioning, and several types of cancer.

A recent French study examined the link between inflammation and diet and lifestyle factors. In this population a comparison was done between the effects of DII on physically active men, defined as those getting more than 1 hour of daily walking or other exercise, and those getting irregular or less than 1 hour/day of exercise.  In the less physically active group a higher DII score was associated with 2 times the risk of depressive symptoms but there was no such relationship in those getting more exercise.  A similar risk relationship was found between DII and depression risk in current and former smokers, but not in non-smokers.

Several other studies have found a similar relationship between diet and depression risk.  In large population based studies there is generally a significantly higher risk of depression in both women and men consuming a diet with a higher DII compared to those consuming a lower DII diet.

What sort of foods tend to exert an anti-inflammatory effect?  There are many vitamins that fall into that category, and some of the foods include fiber, garlic, ginger, pepper, onion, and tea.  For a more comprehensive list check out this link. It’s interesting to note that a diet higher in calories is also associated with higher inflammation, more evidence that eating more than what is enough to satisfy hunger may not be a good idea.

There is an ever increasing range of diets out there that cater to different people for different reasons, and different people will have different nutritional requirements.  For people who are looking to reduce their levels of inflammation and thereby reduce their risk for various diseases it seems like the best diet to follow might be one that has a lower Diet Inflammatory Index.

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Folate

When most people hear “folic acid” they think about the need to supplement with it before and during pregnancy. This is because of the well-publicized link between maternal folate status and neural tube defects in newborns. Since more than 50% of pregnancies are unplanned, and the neural tube forms in the first 4 weeks of pregnancy, supplementing with folate after confirming pregnancy could be a bit too late. That’s why in Canada the folic acid fortification of foods was initiated in 1998 and since then the incidence of neural tube defects has decreased by 46%.

Along with vitamins B12 and B6, folate is essential for the synthesis, repair and methylation of DNA.  It is also important in maintaining healthy levels of homocysteine (Hcy).

Moderately elevated levels of Hcy have been found to increase the risk of brain shrinkage, cognitive impairment, and dementia in the elderly.  High levels of Hcy are also correlated with cardiovascular disease and specifically with heart attacks and strokes, and they may contribute to the development of inflammation, and disorders in cholesterol metabolism.  Although genetics can have a significant effect on Hcy levels, it seems that in the majority of cases high levels are due to low vitamin levels or intake.

Folate can come from dietary sources and supplementation.  Some of the major sources of dietary folate are dark green leafy vegetables, fruits, grains, legumes, and dairy products.  The main dietary sources of folate in developed countries are foods that are fortified with synthetic folic acid. Synthetic folic acid has been associated with possible adverse effects, such as masking symptoms of vitamin B12 deficiency and possibly increasing the risk of some cancers.  Consuming synthetic folic acid from supplements or fortified foods, however, is more effective at increasing blood and tissue folate levels than consuming high-folate foods. That’s not to say that consuming dietary folate is not beneficial, just that it may not be adequate in someone who might be folate deficient.

Some research has suggested that high levels of folate may be correlated with various cancers.  This is controversial and making sense of this research is complicated primarily by two things:

  1. Folate levels can be measured either in the serum or in the red blood cell (RBC) and then that there are several different ways that these levels are measured. RBCs retain folate from the time that they are produced through their 120-day life span, so RBC folate levels indicate long-term folate status. The serum levels can change more quickly with folate intake.
  2. The high folate cut-off levels of most of the studies might not be that high and might just be clinically normal levels

What the studies do seem to indicate is that folic acid intake is correlated to lower levels of birth defects, including cardiovascular defects, cleft palate, limb defects, urinary tract malformations, and congenital hydrocephalus. Levels of folate intake that are within the recommended daily intake levels have also been associated with lower levels of colorectal, prostate, breast, and lung cancer in the general population.

There is a portion of the population that has a form of the gene that codes for the enzyme MTHFR C677T that can impair the metabolism of folate and lead to levels of serum folate that are 10–25% lower than in others without that gene variant. This could impact laboratory measures of RBC folate in this population. It’s also interesting to note that there is evidence that in the population with that gene variant, supplementation with 5-MTHF but not with folic acid can lead to increases in 5-MTHF in the cerebrospinal fluid.  This is relevant because some of these people may develop neurological symptoms that can be corrected with 5-MTHF.

Some of the folate in foods is lost by the heat from cooking or by dissolving into the water used to boil them. There is a trade-off, however, as the cooking may also increase the bioavailability, or how much is available for the body to use, of the folate, depending on what form it is in.  There are two major forms that are used in food fortification and supplementation: folic acid and 5-MTHF. The form traditionally added to food is the folic acid form and 5-MTHF is the form that easily utilized within the body. Studies using radio-labelled forms of 5-MTHF and folic acid have shown that levels of folate in the blood are about 50% lower with folic acid than with 5-MTHF for the first couple of hours after oral administration. This could be due to the liver’s affinity for folic acid, as well as several other factors which can affect the bioavailability of folate, including the presence of absorption inhibitors, such as EGCG found in green tea, the pH of the digestive tract, and the genetic variations mentioned earlier. As mentioned earlier, synthetic folic acid can mask the symptoms of a B12 deficiency but the 5-MTHF form of the vitamin is not likely to do so.

As a general guideline, you should make sure that you get adequate levels of folate, preferably in the 5-MTHF form, and don’t take too much, because the possible adverse effects of having too much are unknown. If you’re interested you can also get genetic testing to determine the influence of your particular genetics on your folate status.

 

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There’s No Need To “Stress”

It’s 6:00 a.m. on a Monday morning and the alarm clock goes off. You climb over your partner to hit the snooze button and tell yourself that you are just going to sleep for another ten minutes. To your dismay, you awaken later only to see that it is now 6:45a.m.! You should have been up by 6:00 as you need to leave the house by 7:15a.m. to get to work. In a mad rush, you jump out of bed (even though your whole body feels stiff), brush your teeth frantically and hop in for a quick shower. Feeling a little lightheaded, with your heart pounding against your chest, you quickly get dressed. You grab your computer and cell phone and get into your car. At that very moment, you feel frustration and anger all over and this is certainly not how you wanted to start the beginning of your week. As you sit in your car, you can feel the tension and knots in your upper shoulders and neck. What should have been a relaxing drive to work becomes a race against the clock. You have not had breakfast and there is no time to even consider stopping for something. Coffee and something from the vending machine will have to do once you get to work. At your desk, you are greeted by a pile of work leftover from last week and you now dread all the additional new work that is going to come your way. This week will be much the same in terms of a hectic schedule: kid’s having their regular extracurricular activities, preparing for a garage sale at the end of the month and trying to organize for a much needed vacation. Why does life have to be so hectic? You think to yourself, why am I always so stressed? Why do I always feel frustrated and angry. Before you sit down to tackle the day, you grab your double double from the office cafeteria and decide to indulge in a cream cheese toasted bagel…you decide on the sesame seed bagel because it’s healthier!

Sound familiar? Indeed, we live in a day and age where it seems life is moving at “roller coaster” pace. We just don’t seem to have the time to sit by a lake to admire nature’s surroundings or even meet with our loved ones. Everyone is busy and you just can’t get each other’s calendars to line up. There is always a sense of falling behind, feeling low energy as everything seems to be such a great effort. When you do try to sleep at night, although you feel physically exhausted and ready to “crash” your mind tells you otherwise. You think to yourself, “how much longer can I go through life feeling like this…feeling wired and tired”

As Naturopathic Doctors, this does seem to be a recurring theme for many patients that come into our office. It is currently estimated that 75% of visits to doctors are due to stress related ailments. In fact, stress is a leading factor in deaths from heart disease, cancer, stroke, lower respiratory diseases and accidents. The good news is, you can do something about it! When you see a Naturopathic Doctor, he or she will help to create a thorough treatment plan for you to help manage your stress. Moreover, the plan would be tailored and customized to your individual needs and health concerns as everyone deals with stress differently; how certain stresses effect one person may not necessarily have the same affect on another. By taking a thorough case intake, performing relevant physical exams along with any pertinent blood testing, a Naturopathic Doctor will be able to create a unique stress management plan for you. It’s all about inspiring you and giving you ownership of your health.

Naturopathic Doctors will often assess your adrenal glands as they are fundamentally the most important when it comes to the stress response. Whenever we have any demand on us, be it “good” or “bad”, the adrenal glands release hormones such as cortisol and adrenaline which help to prepare the body to meet those demands. Short term stress (such as preparing for a job interview, writing an exam), may actually be a good thing as it allows you to “dig deep” and uncover qualities about yourself that you may not have realized in order to accomplish the task or face the situation on hand. The issue is when stress becomes a chronic part of your life, an everyday occurrence. At some point, the adrenal glands can become “over taxed” or as we would term, “adrenal fatigue”

Adrenal fatigue is a set of signs and symptoms that can result when the adrenals glands are functioning below their optimal level. In our practices, we have determined that adrenal fatigue can be associated with intense or prolonged periods of stress, during or after an acute or chronic infection (especially pneumonia, influenza, bronchitis), loss of a loved one or an emotional trauma, and physical trauma to name a few. Some of these signs may include: a sense of feeling unwell, low energy or poor stamina or inability to deal with any tasks at hand, lightheadedness or dizziness, cravings for salt and/or sweet, the need for stimulants such as coffee or “energy drinks” to get you going in the morning and so on. However, it does not have to be this way!

A licensed Naturopathic Doctor will work with you to determine what dietary considerations will be the most important for you to help strengthen those exhausted adrenals. Nutritional supplements such as Vitamin C, Vitamin B5, high quality fish oil to name a few are very critical in helping to address adrenal fatigue. Herbs like Rhodiola and Ashwagandha have consistently proven to be beneficial in optimizing the function of the adrenal glands. Acupuncture treatments may also be recommended – always a welcome addition to the protocol. Not only will acupuncture help to harmonize the flow of qi and thus relieve tension and anxiety, it gives the individual an opportunity to relax for 20-30 minutes. When a proper treatment plan is implemented, patients begin to feel well, look well, sleep better, and have more energy and motivation for life. There is no reason that you should be living your life in a constant state of stress or “always trying to catch up”. Take charge and ownership of your health and see a licensed Naturopathic Doctor. It will be the best decision you will have ever made for your health!