Wednesday, June 10, 2015

The Good Krill & Salmon Oil That's Bad For You: Increased Risk of Metabolic Syndrome in Men Who Supplement

Recent Human Cross-Over Trial Puts "?" Behind Super-Supplement Status of Omega-3 Supplements
Increases in omega-3 intake are among the"small dietary modifications" doctors and nutritionists like to suggest to their patients in their common battle against obesity that are comparatively easy to achieve. It is thus no wonder that millions are enthralled by the cheap fish, krill, cod and salmon oil caps you can buy in every supermarket, these days.

The often (namely when they're rancid) disgustingly tasting content of the pills is believed to offer absolution from all your dietary sins, because epidemiologic (Villegas. 2011; Djouss√©. 2011) and animal evidence suggested that these n–3 PUFAs may in fact improve insulin sensitivity and metabolic risk.
You can learn more about omega-3 & co at the SuppVersity

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For most people the marketing and the existence of the previously cited non-relevant studies (what we want are randomized, double-blinded clinical human trials) are exciting enough to forget about the existing conflicting evidence from randomized controlled trials (Mori. 1999; Ramel. 2008; Tsitouras. 2008):
"A systematic review that included 11 randomized controlled trials and 618 participants concluded that n–3 PUFA supplementation did not influence insulin sensitivity (Akinkuolie. 2011). However, the individual trials were highly heterogeneous and included participants with and without type 2 diabetes and used a wide range of n–3 PUFA sources, doses, and control oils" (Albert. 2015).
What? You don't know about that? Well. I am not surprised, because all you hear about in the mainstream science outlets are the exciting studies, where fish oil is added on top of a weight loss regimen (Mori. 1999; Ramel. 2008), so that no-one can tell you if it's the diet or the fish oil or the fish oil in conjunction with the diet that does the insulin sensitivity improving magic.
Figure 1: Overview of the study design (Albert. 2015).
For krill oil, which is an increasingly popular source of marine n–3 PUFAs that differs from fish oil, because its n–3 PUFAs are predominantly in phospholipid form, while those in fish oil are triglyceride bound (Schuchardt. 2011). In view of the fact that krill oil also contains astaxanthin, which is a carotenoid pigment and powerful antioxidant (Shahidi. 2010), it is thus not surprising that differential effects of krill and fish oils have been described in mice (Burri. 2011).
Something to ponder on: I think it is worth mentioning that the control oil in the study at hand was canola oil. An oil that has actually a quite favorable fatty acid composition compared to stuff like soybean oil or corn oil. So, if you see a study with different results, make sure you check what oil the scientists used in the placebo group.
What is surprising, though is that the effect of krill-oil supplementation on insulin sensitivity in humans has not been reported..., well, at least before Albert et al. investigated whether supplementation with a blend of krill and salmon (KS) oil would lead to changes in insulin sensitivity in a double-blind, randomized, controlled, crossover human trial.
"The design was a randomized, double-blind, controlled crossover trial. A total of 47 men with a mean 6 SD age of 46.5 6 5.1 y, who were overweight [body mass index (in kg/m2) from 25 to 30] but otherwise healthy, received 5 1-g capsules of KS oil or a control (canola oil) for 8 wk and crossed over to another treatment after a 8-wk washout period. The primary outcome was insulin sensitivity assessed by using the Matsuda method from an oralglucose-tolerance test. Secondary outcomes included lipid profiles, inflammatory markers, 24-h ambulatory blood pressure, and carotid artery intimamedia thickness [...]"

The active treatment contained krill oil (88%) and salmon oil (12%). This combined oil was 42.1% of phospholipids by weight, and each 1000-mg gelatin capsule contained 46 mg EPA and 31 mg DHA. Participants were instructed to take 5 capsules as a single dose, once a day, with a glass of water, which equated to a daily supplementation with 400 mg n–3 PUFAs (including 230 mg EPA plus 154 mg DHA). The control intervention consisted of 1000 mg canola oil, which was also presented in a gelatin capsule that was minimally coated in fish oil (,5 mg) to match odor and flavor" (Albert. 2015).
What the scientists (and probably most of you) didn't expect was that the insulin sensitivity (per the Matsuda index) was 14% lower with the KS oil than with the control oil (canola | P = 0.049) - and that despite the fact that the KS oil had a peroxide value (PV) below the lower limit of detection of 0.3 mEq/L and an ansidine value (AV) of 11.0, which indicated a Totox value < 11.6 and indicates that it was as fresh or fresher than any of the best products you can buy.
Figure 2: Primary outcome - Insulin sensitivity (Matsuda index, low values are bad | Albert. 2015)
If you are still not questioning the "health halo" of fish oils, you should know that a mediation analysis the scientists conducted showed that, after controlling for the likely positive effects of blood EPA and DHA (i.e., the omega-3 index), the reduction in insulin sensitivity after KS-oil supplementation was more marked [27% lower than with the control oil (P = 0.009)]. Even the improvements in blood lipids (Total cholesterol, LDL, HDL, Triglycerides, Apolipoprotein A & B) many people who take fish oil are sure they would get, were not observed.

What should be said in favor of the omega-3 supplement is that only the acute insulin sensitivity as it is measured in the Matsuda test was messed up from the krill + salmon supplement. For HOMA-IR and fasting glucose the scientist didn't find a sign. difference... which reminds me that I should mention that this is often the only measure of glucose control in scientific studies (esp. in fish oil studies). In spite of the fact that the Matsuda index provides a much better assessment of how your body actually handles incoming glucose (Matsuda. 1999).
There's something fishy about high dose fish oil supplementation. Increased inflammation and beginning fatty liver disease and a dose-response curve for EPA + DHEA that's U-shaped | read more!
So, basically, the study at hand suggests that the more you increase your omega-3 index, i.e. the total weight of EPA + DHA in your red blood cells divided by the weight of the red blood cells, or, put simply, the better your krill oil + salmon supplement works, the worse it's going to be for your insulin sensitivity.

That's a surprising, but not a contradictory results. After all previous tightly controlled clinical trials on fish oil were unable to confirm any benefit on blood glucose management, too. And in view of the fact that clinical human trials for krill + salmon oil that could contradict the results of the study at hand are non-existant, it's hard to argue with the conclusion the researchers from the University of Auckland and the University of Newcastle draw: "[K]rill-oil supplementation in overweight adults could exacerbate risk of diabetes and cardiovascular" (Albert. 2015).

Things to keep in mind, though are (a) the fact that the subjects were overweight, results in both obese and lean individuals may thus differ (the same could go for the dosage, although 5x1,000mg caps is not much considering the low EPA + DHA content of the oils), (b) the fact that previous studies have shown sign. differences between the effects of fish and fish oil supplements with the former always having the upperhand and (c) the selected measure of insulin sensitivity, the Matsuda index (Matsuda. 1999), which is excellent, but different from static measures like fasting blood glucose or quasi-static ones like HOMA-IR. Data that does not in all cases reflect one's ability to handle glucose correctly; and data to which  the previously cited epidemiological studies are usually limited | Comment on Facebook!
  • Akinkuolie, Akintunde O., et al. "Omega-3 polyunsaturated fatty acid and insulin sensitivity: a meta-analysis of randomized controlled trials." Clinical nutrition 30.6 (2011): 702-707.
  • Albert, Benjamin B., et al. "Supplementation with a blend of krill and salmon oil is associated with increased metabolic risk in overweight men." The American journal of clinical nutrition (2015): ajcn103028.
  • Burri, Lena, et al. "Differential effects of krill oil and fish oil on the hepatic transcriptome in mice." Frontiers in genetics 2 (2011).
  • Djouss√©, Luc, et al. "Plasma omega-3 fatty acids and incident diabetes in older adults." The American journal of clinical nutrition 94.2 (2011): 527-533.
  • Matsuda, Masafumi, and Ralph A. DeFronzo. "Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp." Diabetes care 22.9 (1999): 1462-1470.
  • Mori, Trevor A., et al. "Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects." The American journal of clinical nutrition 70.5 (1999): 817-825.
  • Ramel, A., et al. "Beneficial effects of long-chain n-3 fatty acids included in an energy-restricted diet on insulin resistance in overweight and obese European young adults." Diabetologia 51.7 (2008): 1261-1268.
  • Schuchardt, Jan Philipp, et al. "Incorporation of EPA and DHA into plasma phospholipids in response to different omega-3 fatty acid formulations–a comparative bioavailability study of fish oil vs. krill oil." Lipids Health Dis 10.145 (2011): 1-7.
  • Shahidi, Fereidoon, and Ying Zhong. "Lipid oxidation and improving the oxidative stability." Chemical Society Reviews 39.11 (2010): 4067-4079.
  • Tsitouras, P. D., et al. "High omega-3 fat intake improves insulin sensitivity and reduces CRP and IL6, but does not affect other endocrine axes in healthy older adults." Hormone and metabolic research 40.3 (2008): dh199-205.
  • Villegas, Raquel, et al. "Fish, shellfish, and long-chain n− 3 fatty acid consumption and risk of incident type 2 diabetes in middle-aged Chinese men and women." The American journal of clinical nutrition 94.2 (2011): 543-551.