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Is it really bad to drink that whey shake before you eat the bananas, strawberries and blueberries, because whey makes you insulin resistant? Sounds "bogussy" and a closer look at the questionable methodological choices of the scientists who conducted the study don't make the results sign. more credible.

In the fitness community, whey protein is the #1 on the "must have supplement" list. Multi-vitamins? Creatine? Who cares, as long as you get your 30g of whey per day, you're good... really? One of you recently send me a study that would suggest that "good" is not exactly the right word to describe the effects of whey protein on at least one out of the set of well-established parameters of optimal metabolic health: Your muscles' insulin sensitivity.

In the paper that has been published in the reputable scientific journal "Diabetes", Gordon I. Smith and colleagues describe an experiment the results of which clearly suggest that whey doesed at 0.6g/kg fat free mass has a sign. insulin-desensitizing effect in twenty-two sedentary (<1.5 hour of exercise/w) and weight-stable (<2 kg change for at least 6 months), 50-65y old postmenopausal women who participated in this acute response study.
Acute response? Yes, there it is, the first in a line of problems that reduces the significance of the results. After all, testing the acute response to a certain health cannot tell you anything about the long-term effects on said parameter... especially if your subject group due to being sedentary and in an age where the parameter in question is deteriorating, anyway.

But let's not be the "it's not bros, so it's not valid for bros"-guys. Let's rather take a look at (a) the procedures and (b) the results and make up our minds later. And let's first take a look at a handful of important parameters of the study design: To determine the insulin sensitivity, the scientists used two hyperinsulinemic-euglycemic clamp sessions with the subjects being randomly assigned to do the procedure with vs. without whey protein first.

If you've got brawn and brain you cannot ignore that whey is much more than a potent muscle builder | learn more

"Before each clamp procedure, subjects were instructed to adhere to their usual diet and to refrain from vigorous physical activities for three days. Subjects were admitted to the Clinical Research Unit in the late afternoon, where they consumed a standard dinner between 1800 and 1900 h, and then fasted, except for water, until the next morning. At 0600 h, a catheter was inserted into an arm vein for the infusion of a stable isotope labeled glucose tracer; catheters for blood sampling were inserted into the radial artery of the opposite arm and in retrograde fashion into the femoral vein of one leg. At ~0645 h, a primed, constant infusion of [6,6- 2 H2]glucose (priming dose: 22 µmol·kg body wt-1, infusion rate: 0.22 µmol·kg body wt-1·min-1), purchased from Cambridge Isotope Laboratories Inc. (Andover, MA), was started and 4 h later the hyperinsulinemic-euglycemic clamp procedure was initiated with two 5-minute priming doses (first 200 mU·m-2 body surface area (BSA)·min-1 then 100 mU·m-2 BSA·min-1) of human insulin (Novolin R, Novo Nordisk, Princeton, NJ); for the remaining 230 min, insulin was infused at a rate of 50 mU·m-2 BSA·min-1. Euglycemia (at blood glucose concentration ~5.6 mM) was maintained by variable rate infusion of 20% dextrose (Baxter, Deerfield, IL) enriched to 2.5% with [6,6-2H2]glucose" ().

During the "whey trials", the subjects consumed 0.6 g of whey protein (unflavored Unjury®, ProSynthesis Laboratories, Inc, Reston, VA) per kg FFM dissolved in 360 ml water or the same volume of water alone. In addition, the researchers conducted a trial in which the subjects consumed the same amount of leucine.
To figure out if any effect they would observe was induced by whey, i.e. a complex protein, or just the most-applauded whey ingredient, i.e. leucine, the scientists ran a follow-up test (1-4 weeks later) in which the subjects consumed either 0.0684 g/kg FFM of pure leucine (that's equivalent to the amount of leucine in the whey protein)  dissolved in 360 ml Kool-Aid® (Kraft 94 Foods, Inc, Northfield, IL) or the same volume of the Kool-Aid® solution alone during the clamp procedure. I don't have to tell you that this was a mistake that makes the results of this follow-up useless for comparisons to the previous trial, in which the whey protein was mixed with water - Kool-Aid is after all all-carbohydrate - with 0.9g carbohydrates per ml of junk... ah, I mean per ml of the soft-drink.

Figure 1: Clearance of glucose during the hyperinsulemic clamp for the whole body and the legs (Smith. 2015). It is noteworthy that there control vs. active treatment signalling protein response (mTOR, p-AKT, ACC, etc. - not shown in figure) did not show differences that could explain the alleged negative effects of whey on glucose uptake (see Figure 2).

This does not mean that we couldn't use the data from the leucine trial, at all, though. But let's be honest, who cares about the non-significance of the effects of a non-gluconeogenic amino acid (meaning that leucine cannot be converted to glucose by the liver) if you cannot compare them to the significant decrease in insulin-mediated glucose disposal (38.8 vs 51.9 µmol glucose per µU insulin/ml / min; P<0.01) the scientists observed in the whey condition, because the test was messed due to the use of a different and by no means "neutral" control?

Figure 2: Don't worry, while the scientists cleverly call the glucose disappearance into the legs "leg glucose uptake" it's just the product of blood flow to the legs times whole body glucose disposal and suffers from the same methodological short-come as the whole body glucose disposal that assumes that whey was non-gluconeogenic (data from Smith. 2015)

Rather than as a basis to argue that whey is bad and leucine is good, you can use the Kool-Aid glitch and the fact that leucine cannot be converted to glucose in the liver to substantiate the following hypothesis: If the scientists had accounted for the gluconeogenic glucose load from whey when they tested their allegedly sugar-free (manufacturer claim) whey protein vs. water in the previous trial, they would probably have found no significant effect of whey protein on muscular glucose uptake, because the test wouldn't have been unfairly thwarted in favor of the water control which came without the additional glucose load from the whey-induced gluconeogenesis in the liver.

Figure 3: Both, acute and chronic realistic and thus relevant studies show beneficial effects of whey on glycemia (Petersen. 2009) and insulin sensitivity (Pal. 2010) - you decide which studies to trust ;-)

Plus, even if we assume that this hypothesis wasn't true (I am pretty convinced it is), the results of the study at hand would still be an inexplicable artifice that stands in stark contrast to the well-proven multi-facetted acute and chronic beneficial effects of whey protein on glucose- and weight-management in healthy, diabetic and pre-diabetic individuals (Layman. 2004; Frid. 2005; Peterson. 2009; Akhavan. 2010; Pal. 2010) - effects of which no one ever claimed that they were mediated by acute increases in muscular insulin sensitivity, by the way; and that despite the fact that the data from Pal (Figure 3, left) clearly indicates that these benefits occur in the real world.

References:

• Akhavan, Tina, et al. "Effect of premeal consumption of whey protein and its hydrolysate on food intake and postmeal glycemia and insulin responses in young adults." The American journal of clinical nutrition 91.4 (2010): 966-975.
• Frid, Anders H., et al. "Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects." The American journal of clinical nutrition 82.1 (2005): 69-75.
• Layman, Donald K., and Jamie I. Baum. "Dietary protein impact on glycemic control during weight loss." The Journal of nutrition 134.4 (2004): 968S-973S.
• Morifuji, Masashi, et al. "Dietary whey protein increases liver and skeletal muscle glycogen levels in exercise-trained rats." British journal of nutrition 93.04 (2005): 439-445.
• Pal, Sebely, Vanessa Ellis, and Satvinder Dhaliwal. "Effects of whey protein isolate on body composition, lipids, insulin and glucose in overweight and obese individuals." British journal of nutrition 104.05 (2010): 716-723.
• Petersen, Brent L., et al. "A whey protein supplement decreases post-prandial glycemia." Nutr J 8.47 (2009): 1475-2891.
• Smith, Gordon I., et al. "Protein ingestion induces muscle insulin resistance independent of leucine-mediated mTOR activation." Diabetes 64.5 (2015): 1555-1563.

You don't need supplemental K, well... unless you are on a protein modified fast without fruits and veggies ;-)

The 1984 study by Norbiato et al. is not a very recent, but it's probably a very important study which was set up to investigate "the role of potassium deficiency in the development of glucose intolerance during caloric deprivation" (Norbiato. 1984).

Or, put simly, the scientists wanted to know if a low potassium level may promote insulin resistance and modify or is modified in response to dieting (in this case protein-modified fasting). In the study, two groups of subjects were studied. The "normal" group consisted of ten subjects, who were 27-45 years old and whose body weights ranged from 89 to 115% of the "ideal body weight". The "obese" group group consisted of twenty subjects aged 21-48 years who were 70%-131% overweight.
Before the obese subjects were put on a protein modified fast (PMF) all subjects, lean or obese, received a "weight-maintaining diet" with 200g/day carbohydrates for 8 days.

Figure 1: Macronutrient composition of the ~380kcal PMF diet (Norbiato. 1984).

"The diets were calculated according to individual tastes, employing varying proportions of egg white, beef tenderloin, skim-milk cheese and water-packed canned tuna. For the PMF, total calories varied from a mean of 350-399 in individual subjects, with a mean of 378+/-36 (SD) 

[...] Calculated protein intakes, according to standard tables, were 70.8+/-7.6 g/day (about 79% of calories). Calculated fat intake was 5.7+/-3.5 g /day (19% of calories). Carbohydrate contributed 3.2+/-1.3 g/day, 2% of caloric input" (Norbiato. 1984).

As far as its potassium content is concerned the PMF diet was (as probably most diets that are almost exclusively protein) on the skinny side (15 +/- 3.9 mmol of potassium/day | adult men and women should get 100mmol/day and 72mmol/day, that's 3,800mg and 2,800mg/day or 8-9 bananas if you want to "go bananas" instead of leafy greens ;-). Nevertheless, only 10 out of 20 of the obese subjects received an oral potassium chloride (64 mmol/day) supplement (KC1-retard, Zyma, Italy). The other ten patients received identical placebo tablets.
Interestingly, the potassium levels dropped in both groups during fasting. More importantly, though, the decrease in potassium was associated with a sign. reduction in peripheral levels of insulin along with an increase in insulin receptors and a striking reduction of peripheral glucose utilization in the obese subjects on their protein modified fast.

Figure 2: Mean integrated area under the glucose tolerance test curve in obese subjects submitted to protein-modified fast (PMF) with or without oral KCl supplementation (K): studies were performed in the control period after a 14-day fast and after after 10 days of refeeding with a diet containing 700 kcal (45% carbohydrate) per day (Norbiato. 1984).

Increase in insulin receptor binding and impaired glucose management? How does this go together? Well, if the receptor does not respond, it is no wonder that the researchers found that their subjects ability to handle glucose was significantly impaired in the euglycaemic clamp study.
References:

• Norbiato, Guido, et al. "Effects of potassium supplementation on insulin binding and insulin action in human obesity: protein‐modified fast and refeeding." European journal of clinical investigation 14.6 (1984): 414-419.
• Rowe, John W., et al. "Effect of experimental potassium deficiency on glucose and insulin metabolism." Metabolism 29.6 (1980): 498-502.

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; Djoussé. 2011) and animal evidence suggested that these n–3 PUFAs may in fact improve insulin sensitivity and metabolic risk.
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).
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).
References:

• 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).
• Djoussé, 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.