Why do I feel so lousy? Low-grade inflammation is a cause
Ryan Bradley, ND, MPH September, 2016
Feel “off” and just don’t know why? Tired of people telling you to get more exercise, but feel terrible every time you try? Is there something about diabetes itself that may be causing this feeling, or is it all in your head? Do other people with diabetes suffer from this same yucky, ill feeling malaise?
If so, you are not alone. Fatigue is the third most common symptom in individuals with type 2 diabetes (sadly acute and chronic pain are the two most common symptoms), and is estimated to affect at least 25% of individuals with type 2!1
Fatigue, interchangeable with terms like: sleepiness, tiredness, malaise, lacking energy, and exhaustion, impacts the ability to perform physical and mental tasks, including adopting healthier behaviors.2 Interestingly, when people with type 2 diabetes are compared with patients with type 1 diabetes, people with type 2 report higher levels of general and physical fatigue, and reduced activity, relative to their type 1 counterparts.3 Notably, disturbed sleep and depression frequently accompany fatigue and thus there is an on-going scientific discussion as to whether depression is a cause, or consequence, of chronic fatigue.7
Why are individuals with type 2 more prone to fatigue?
There are many potential causes of fatigue that should not be overlooked. Common causes include:
- B-vitamin deficiency, including B-12 deficiency (which can be caused by diabetes medications like metformin)4
- Dietary indiscretions
- Concomitant liver and/or renal concerns
- Medications such as antidepressants, beta-blockers, opioids, and statins
Specific to individuals with type 2, significant predictors of fatigue include:5,6
- Number and severity of diabetes symptoms
- Diabetes-related emotional distress
- Presence of depression
- Low physical activity
- Elevated BMI
Yet, many people with diabetes have addressed these potential causes, and yet still suffer from a general ill-feeling that impacts their desire to exercise, be socially active, and even engage in life activities more. There must be another cause…
One frequently overlooked cause of fatigue is chronic low-grade inflammation.
The physical feeling associated with this type of fatigue often resembles a mild cold or flu. You know that period early on when you get a cold when you don’t feel quite “right”, maybe a little weak? And it may be hard to clear your thoughts and focus? Can’t quite place the cause? The cause is your immune system!
Where does chronic low-grade inflammation come from?
We have two types of immunity: (1) innate and (2) acquired or adaptive. We are born with our “innate” immunity and it first serves as our first line of defense to threats such as bacteria and viruses. Our adaptive immunity, which evolves over time in response to different “offenders”, is informed and controlled by our innate immune system.
When the innate immune system is activated, there is an inflammatory response, and messengers called “acute phase reactants” are released into the blood stream.7 These messengers include compounds called “C-reactive protein (CRP)”, “interleukin-6 (IL-6)”, and “tumor necrosis factor-α (TNF-α)”.
These reactions are helpful for the body to target infections and facilitate healing, however, during these reactions the body shuts down other bodily functions and causes symptoms such as fatigue, and also changes in sleep and mood. These symptoms are helpful in the short-term for the immune system to do its job, to slow us down, and encourage us to get the rest we need, and not “over do it”.
However, if the immune system is chronically activated, such as can result from high blood sugars in diabetes,7 these symptoms do not resolve and lead to life-altering chronic, debilitating fatigue. The messengers CRP, IL-6, and TNF-α mediate these physical symptoms in conditions like obesity, type 2 diabetes, and metabolic syndrome, just as they do in physical trauma or some infections.8 When these proteins are released, they promote fatigue, depressive symptoms, impair brain function (including being able to think clearly), sleep problems, and even increased pain sensitivity.8,9
Are there treatments for chronic, low-grade inflammation?
Not surprisingly, the degree of low-grade inflammation is directly tied to elevations in blood sugar. Therefore, adopting behaviors that help lower and manage blood sugar, including more physical activity and reducing consumption of high carbohydrate, refined and processed foods always help!
The relationship between exercise and inflammation is complex. In the short term, and especially from strenuous exercise, exercise can actually increase many of the same inflammatory messengers that are elevated in diabetes.10 However, numerous research studies have demonstrated that in the long-term, exercise clearly lowers inflammation, including IL-6, CRP, and TNF-α.11 Still many people with diabetes feel terrible after beginning to exercise more strenuously- it is very likely that they have compounded their inflammatory messengers and actually worsened how they feel! (Said differently, it may be best to first reduce inflammation before trying to change or increase exercise intensity- you will likely feel better and be more likely to return to exercise as a means to control your blood sugar!).
Some medications have “anti-inflammatory” properties as well, including: aspirin, thiazolidinediones, and statins. However, each of these medications can also have debilitating side effects including stomach ulcers, weight gain, and muscle pain respectively.7,12–14
However, directly managing your immune response may be an effective approach to reduce symptoms like fatigue. Notably, clinical trials also support the use of several natural dietary supplements for reducing low-grade immune-mediated fatigue. These natural products include:
- Green Tea Extract (GTE), made from green tea leaves rich in the polyphenol “ECGC”, can reduce TNF-α and CRP concentration in the blood, and thus may be beneficial for fatigue in diabetes. A randomized controlled trial (RCT) by Bogdanski et al. in 56 overweight people with high blood pressure demonstrated that daily supplementation with 379 mg of GTE for 3 months significantly lowered TNF-α and CRP levels compared to placebo. Additionally, they found improvements in antioxidant status, insulin sensitivity, triglyceride and cholesterol levels, and blood pressure!15
- Resveratrol, a polyphenol constituent found in red and purple grapes, may also be helpful in reducing the immune-messengers that cause fatigue. Specifically, Tome-Carneiro et al. found a resveratrol-rich grape supplement (including 8mg of resveratrol) taken at a single dose for 6 months and double dose for 6 months decreased CRP and TNF-α and in 25 people who were taking statins and at high-risk for heart disease.18 Similarly, 13 men with high blood pressure and type 2 diabetes experienced a significant reduction of IL-6 and TNF-α after taking a resveratrol enriched grape extract daily for 1 year.19
- Curcumin, found in the spice turmeric, adds to this palette of “polyphenolic” compounds that can reduce CRP, IL-6 and/or TNF-α in people with type 2 diabetes. A randomized trial including 67 patients with type 2 demonstrated significant reductions of IL-6 and TNF-α after taking 150 mg of curcumin twice daily for 8 weeks.21 In a separate clinical trial 50 people with type 2 took curcumin for 3 months, and had subsequent reductions in in CRP, TNF-α, and IL-6, plus improved metabolic parameters in comparison to 50 participants taking a placebo.22
- N-acetylcysteine (NAC), a precursor to the antioxidant glutathione, reduced IL-6 and CRP in people with renal failure who were on dialysis. 23, 24 Although not specific to people with diabetes, these human clinical studies demonstrate the potential and safety for NAC in a vulnerable group of people.
So, if you, or others you know with diabetes, just don’t feel quite as energetic as you would like, and other causes of fatigue have been ruled out by you and your physician, low-grade inflammation may be the culprit! Although dietary increases in green tea, use of turmeric spice in food, and intake of grapes/grape juice/red wine may help, it is also difficult to get the same dosages from food as have been tested in clinical research for people with diabetes. Trying dietary supplements with these ingredients may be helpful, and these compounds appear to be well tolerated with few reported side effects. As always, discuss all nutritional supplementation with your physician, especially if you take blood thinning medications, are on dialysis, or have “lows” in your blood sugar or blood pressure.
Regardless of whether you try these supplements or not, it is important to know that the symptom of fatigue (along with disrupted sleep, depressed mood, and brain fog) are common symptoms in people with type 2 diabetes, and they have a real physical cause- chronic inflammation!
In health, Ryan Bradley, ND, MPH
1. Sudore RL, Karter AJ, Huang ES, et al. Symptom Burden of Adults with Type 2 Diabetes Across the Disease Course: Diabetes & Aging Study. J Gen Intern Med. 2012:1-8. doi:10.1007/s11606-012-2132-3.
2. Fritschi C, Quinn L. Fatigue in patients with diabetes: A review. J Psychosom Res. 2010;69(1):33-41. doi:10.1016/j.jpsychores.2010.01.021.
3. Lasselin J, Layé S, Barreau J-B, et al. Fatigue and cognitive symptoms in patients with diabetes: Relationship with disease phenotype and insulin treatment. Psychoneuroendocrinology. 2012;37:1468-1478. doi:10.1016/j.psyneuen.2012.01.016.
4. Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2016. doi:10.1016/j.diabet.2016.03.008.
5. Fritschi C, Quinn L, Hacker ED, et al. Fatigue in women with type 2 diabetes. Diabetes Educ. 2012;38(5):662-672. doi:10.1177/0145721712450925.
6. Park H, Park C, Quinn L, Fritschi C. Glucose control and fatigue in type 2 diabetes: the mediating roles of diabetes symptoms and distress. J Adv Nurs. 2015;71(7):1650-1660. doi:10.1111/jan.12632.
7. Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004;27(3):813-823. doi:10.2337/diacare.27.3.813.
8. Lasselin J, Capuron L. Chronic low-grade inflammation in metabolic disorders: Relevance for behavioral symptoms. Neuroimmunomodulation. 2014;21(2-3):95-101. doi:10.1159/000356535.
9. Lasselin J, Layé S, Dexpert S, et al. Fatigue symptoms relate to systemic inflammation in patients with type 2 diabetes. Brain Behav Immun. 2012;26(8):1211-1219. doi:10.1016/j.bbi.2012.03.003.
10. Pedersen BK, Steensberg A, Schjerling P. Exercise and interleukin-6. Curr Opin Hematol. 2001;8(3):137-141. http://www.ncbi.nlm.nih.gov/pubmed/11303145. Accessed September 7, 2016.
11. Hayashino Y, Jackson JL, Hirata T, et al. Effects of exercise on C-reactive protein, inflammatory cytokine and adipokine in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Metabolism. 2014;63(3):431-440. doi:10.1016/j.metabol.2013.08.018.
12. Iwamoto J, Saito Y, Honda A, Matsuzaki Y. Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy. World J Gastroenterol. 2013;19(11):1673-1682. doi:10.3748/wjg.v19.i11.1673.
13. Defronzo RA, Mehta RJ, Schnure JJ. Pleiotropic effects of thiazolidinediones: implications for the treatment of patients with type 2 diabetes mellitus. Hosp Pract (1995). 2013;41(2):132-147. doi:10.3810/hp.2013.04.1062.
14. Brinton EA, Maki KC, Jacobson TA, Sponseller CA, Cohen JD. Metabolic syndrome is associated with muscle symptoms among statin users. J Clin Lipidol. 10(4):1022-1029. doi:10.1016/j.jacl.2016.05.003.
15. Bogdanski P, Suliburska J, Szulinska M, Stepien M, Pupek-Musialik D, Jablecka A. Green tea extract reduces blood pressure, inflammatory biomarkers, and oxidative stress and improves parameters associated with insulin resistance in obese, hypertensive patients. Nutr Res. 2012;32(6):421-427. doi:10.1016/j.nutres.2012.05.007.
16. Fukino Y, Shimbo M, Aoki N, Okubo T, Iso H. Randomized controlled trial for an effect of green tea consumption on insulin resistance and inflammation markers. J Nutr Sci Vitaminol. 2005;51(5):335-342. doi:10.1038/sj.ejcn.1602806.
17. Sueoka N, Suganuma M, Sueoka E, et al. A new function of green tea: prevention of lifestyle-related diseases. Ann N Y Acad Sci. 2001;928:274-280. doi:10.1111/j.1749-6632.2001.tb05656.x.
18. Tome-Carneiro J, Gonzalvez M, Larrosa M, et al. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am J Cardiol. 2012;110(3):356-363. doi:10.1016/j.amjcard.2012.03.030.
19. Tome-Carneiro J, Larrosa M, Yanez-Gascon MJ, et al. One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res. 2013;72:69-82. doi:10.1016/j.phrs.2013.03.011.
20. Brasnyó P, Molnár GA, Mohás M, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011;106(3):383-389. doi:10.1017/S0007114511000316.
21. Usharani P, Mateen AA, Naidu MUR, Raju YSN, Chandra N. Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study. Drugs R D. 2008;9(4):243-250. http://www.ncbi.nlm.nih.gov/pubmed/18588355. Accessed September 2, 2016.
22. Na LX, Yan BL, Jiang S, Cui HL, Li Y, Sun CH. Curcuminoids Target Decreasing Serum Adipocyte-fatty Acid Binding Protein Levels in Their Glucose-lowering Effect in Patients with Type 2 Diabetes. Biomed Environ Sci. 2014;27(11):902-906. doi:10.3967/bes2014.127.
23. Nascimento MM, Suliman ME, Silva M, et al. Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: A placebo-controlled study. Perit Dial Int. 2010;30(3):336-342. doi:10.3747/pdi.2009.00073.
24. Saddadi F, Alatab S, Pasha F, Ganji MR. The Effect of Treatment with N-acetylcysteine on the Serum Levels of C-reactive Protein and Interleukin-6 in Patients on Hemodialysis. Saudi J Kidney Dis Transplant. 2014;25(1):66-72. doi:10.4103/1319-2442.124489.