Whey Beyond Brawn: 10+ Things You Probably Didn't Know Whey & Peptides That Form During its Digestion Can Do: From A as in Vitamin A Uptake to Z as in CanZer Protection

If you've got brawn and brain you will realize that whey is much more than a potent muscle builder.
As a SuppVersity reader, you are well familiar with the pluripotent benefits whey protein has to offer to the average and extra-ordinary gymrat. You will also be aware that it can promote weight loss and help you maintain lean muscle mass when you're dieting.

If you've read almost all ~2,000 SuppVersity articles, you will even know about the GLUT4 and thus glucose uptake promoting effects isoleucine containing dipeptides in whey protein hyrolysates, but I guess that some of the other benefits whey protein owes to its complex mixture of proteins and peptides are going to be news for you.
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In their latest paper in the Austin Journal of Nutrition and Food Science Rie Tsutsumi and Yasuo M. Tsutsumi provide a concise overview of the biological effects of a range of peptides and proteins in whey protein. The latter include...
  • Amino acid composition of whey, casein and breast milk - whey excells in terms of pro-anabolic BCAAs (McDonough. 1974)
    whey is the richest natural source of BCAA -- I don't have to tell you that, but I thought maybe there is someone who has never heard of it before ;-)
  • whey protein has the highest biological value (indicative of the most balanced EAA profile) of all dairy proteins (the  biological  value  is  the  ratio  of  the amount of nitrogen that is consumed to the amount of nitrogen that is absorbed, and this value is 74 for soy protein, 71 for casein, and 104 for whey protein)
  • whey protein has the highest protein efficacy ratio, i.e. the body weight increase associated with an intake of 1 g protein is 3.0 (vs. 2.0 for soy protein and 2.5 for casein protein)
Whey proteins are however far more than building blocks / muscle builders, the  proteins  in  whey  have a variety of roles and immune-related functions:
  • b-lactoglobulin binds retinol (vitamin A) and promotes uptake of retinol via gut; by a similar mechanism it may also facilitate the uptake of long-chain fatty acids
  • a-lactoalbumin kills tumour cells (in vitro) and exerts anti-bacterial effects in the upper respiratory systems; it has also been shown to have protective effects on gastric mucosa.
  • Table 1: Content of minor bioactive proteins in whey concentrates (levels are probably lower in iso- and hydrolysates | values from Smithers. 2008) and the lactalbumin fractions. Since the major proteins in whey (not listed here) can form bonds with albumin (Havea. 2001), whey is another case, where an increase in processing may lead to a decrease in beneficial biological activity.
    lactoferrin regulates the absorption of iron via gut; it will inhibit the growth of various bacteria and regulates immunological response of immunocomponent cells
  • serum albumin binds and carries fatty acids and bile pigment
  • immuno-globulin G involves with bactericidal (anti-bacterial) effects with complements and prevents bacteria from adhering to tissues; neutralizes toxins and viruses
  • immuno-globulin A inhibits growth of various bacteria by condensing them; prevents bacteria from adhering to the surface of mucosa; neutralizes toxins produced by viruses and bacteria.
  • immuno-globulin M has the same effects as IgG, but its bioactivity is stronger
  • lactoperoxidase catalyzes the reaction of producing cyanogen ion with strong bactericidal power from cyanic ion and hydrogen peroxide in the body
  • lysozyme kills bacteria by destroying cell walls
As the Japanese researchers point out, the mechanisms relating to the whey functions are varied. The antioxidant and detoxifying activity of whey is most likely linked to its contribution to GSH synthesis.
"Cysteine, which contains an antioxidant thiol group, combines with glycine and glutamate to form GSH. GSH is the major endogenous antioxidant produced by cells, providing production for RNA, DNA, and proteins via its redox cycling from the reduced form, GSH, to the oxidized form, GSSH. Though direct conjugation, GSH detoxifies a host of endogenous and exogenous toxins including toxic metals, petroleum distillates, lipid peroxides, bilirubin, and prostaglandins." (Tsutsumi. 2014)
The antioxidant and antimicrobial effects of lactoferrin have already been mentioned above. In addition, lactoferrin demonstrates an ability to stimulate immune responses involving natural killer cells, neutrophils, and macrophage cytotoxicity. Furthermore, a mouse study concluded that lactoferrin acts as an anti-inflammatory by regulating the levels of tumor necrosis factor and interleukin-6.
"Owing to its ability to chelate iron, organisms requiring iron for replication appear to be particularly vulnerable to the effects of lactoferrin. The protein beta-lactoglobulin contains anti-hypertensive peptides, which lower blood pressure as significantly as angiotensin converting enzyme (ACE) inhibitors. Cholesterol-lowering effects have also been noted as a result of changes in micellar cholesterol solubility in the intestine." (Tsutsumi. 2014)
Moreover, the formation of peptides through the hydrolysis of whey proteins in your tummy is a rather novel, but very interesting effect that may well contribute to the beneficial health effects of whey proteins. In fact, whey peptide is one of the major peptides that inhibit ACE (FitzGerald. 2004), which induces blood-pressure regulating effects.

It is very likely that peptides are also responsible for many of the metabolic benefits

Pal et al. demonstrated a decrease in fasting plasma concentrations of triacylglycerols after long-term whey protein intake (12 weeks) in overweight and obese individuals (Pal. 2010a,b,c). And while the mechanisms behind the effects of whey protein on triacylglycerols are not understood, Mortensen et al. proposed that a meal containing whey might have resulted in reduced production of chylomicrons and accelerated chylomicron clearance resulting from the stimulation of lipoprotein lipase by whey.
Figure 2: Changes in insulin and HOMA-IR (insulin resistance) insulin response to 12 weeks on 27g of whey vs. casein (vs. control) in overweight / obese subjects (Pal. 2010b)
This would yet not explain the significant improvements in glucose management evidenced by reduced insulin and HOMA-IR values in the whey group of Pal et al.'s 12-week intervention with 27g of whey (vs. glucose vs. casein; cf. Figure 2).

Pal et al. are obviously not the only ones, who observed significant beneficial effects on glucose management in response to the ingestion of whey protein supplements. As Tsutsumi & Tsutsumi point out "[t]he majority of these studies reported that whey protein intake decreases blood glucose and insulin levels" (Tsutsumi. 2014)

Whey a source of bioactive anti-diabetic, pro-satiety peptides?

The latter is interesting, because we know that in type II diabetics, whey protein will increase not decrease the insulin response. I that, the acute effects of whey protein on postprandial blood glucose are comparable to sulfonylureas and other insulin secretagogues used for the pharmaceutical management of hyperglycemia in type 2 diabetes. A benefit that is probably related to bioactive peptides and amino acids that are generated during gastrointestinal digestion and enhance the release of several hormones (including insulin) which are able to reduce the food intake and increased satiety (e.g. cholecystokinin, peptide YY, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1)). How exactly this works is still being researched, but both, ...
  • Figure 3: Effects of 48 g casein (full circles) or whey (open squares) on GLP-1 (Hall. 2003)
    the production of bioactive peptides that serve as endogenous inhibitors of dipeptidyl peptidase 4 in the proximal gut, preventing the degradation of the insulinotropic incretins GLP-1 and GIP, as well as ...
  • a mechanism that involves BCAAs, specifically leucine, which activates the mTOR signaling pathway and protein synthesis leading to elevated hormone expression and secretion and increased thermogenesis
...have been brought forward and supported by research. In the end, it does not really matter how whey does it. The resulting increases in satiety, thermogenesis, and reduction of blood glucose, which is comparable to pharmaceutical treatment, support the use of whey protein in the management of type 2 diabetes and obesity, anyway.
I won't bore you with the muscle building effects of whey: You just have to click here to see previous articles on whey protein, if you actually feel you need to know more about the muscle-building prowess of whey protein.
If whey protein helps prevent or even cure diabesity it will also help to prevent a hell lot of the side effects of being an overweight type II diabetic. And still, researchers believe that there may be a more direct link than diabesity prevention to the following health benefits of whey protein that are listed in Tsutsumi & Tsutsumi's latest review (the following bulletpoints are in large parts direct quotes from Tsutsumi. 2014):
  • cancer  -- A number of animal studies have examined the anti-cancer potential of whey, believed to be primarily associated with the antioxidizing, detoxifying, and immune-enhancing effects of GSH and lactoferrin.

    A few clinical trials have been undertaken, proposing that high levels of GSH in tumor cells confer resistance to chemotherapeutic agents. One of these studies showed that 20 patients with stage IV malignancies were treated daily with 40 g whey in combination with supplements such as ascorbic acid and a multi-vitamin/mineral formulation (See. 2002). The 16 survivors demonstrated increased levels of natural killer cell function, GSH, hemoglobin, and hematocrit 6 months later. An aggressive combination of immunoactive nutraceuticals was effective in significantly increasing natural killer function, other immune parameters, and plasma hemoglobin in patients with late stage cancers.
  • hepatitis B & C -- The results of trials for the hepatitis B virus have been positive,  particularly  those  from  an  open  study  that  included  8  patients administered 12 g non-heated whey/day. The patients demonstrated improved liver function markers, decreased serum lipid peroxidase levels, and increased  interleukin-2  and  natural  killer  cell  activity (Watanabe. 1999)

    Regarding hepatitis C, several trials have proved inconclusive, although an initial in vitro study found that bovine lactoferrin prevented the hepatitis C virus in a human hepatocyte line (Ikeda. 1998)
  • Figure 4: Next to reductions in blood pressure, whey induced reductions in blood lipids are a likely mechanism behind the reduced CVD risk with whey (illustration from Pal. 2013)
    cardiovascular disease -- According to the results of a number of studies, intake of milk and milk products can lower blood pressure and reduce the risk of hypertension (Marshall. 2004). Kawase et al. performed an 8-week trial in which 20 healthy men were given a combination of fermented milk and whey protein concentrate and examined the effect on serum lipids and blood pressure (Kawase. 2000). After the 8 weeks, the fermented milk group demonstrated comparatively higher high-density lipoproteins, lower triglycerides, and lower systolic blood pressure. 
  • hypertension --Various investigators have hypothesized that certain bioactive peptides formed through the hydrolysis of food proteins have the ability to inhibit ACE, and this subject has been comprehensively reviewed in a number of studies. In general, it has been claimed that a diet rich in foods containing anti-hypertensive peptides is effective for the prevention and treatment of hypertension. ACE-inhibitory peptides may be obtained from precursor food proteins via enzymatic hydrolysis, the use of viable or lysed microorganisms, or specific proteases.

    However, studies relating to whey peptides with ACE inhibitory activities are more limited; this may be due to the rigid structure of beta-lactoglobulin, which makes it particularly resistant to digestive enzymes. 
  • osteoporosis -- Milk basic protein (MBP) is a component of whey that demonstrates the ability to not only suppress bone resorption but also stimulate proliferation and differentiation of osteoblastic cells (Marshall. 2004).

    The role of calcium intake in determining bone mineral mass is well recognized to be the most critical nutritional factor to achieve optimal peak bone mass; milk protein is also important for preventing osteoporosis. A number of clinical trials support milk protein’s positive effects in both men and women, the latter ranging in age from young to postmenopausal. Daily doses of 40 mg MBP (equivalent to 400–800 mL milk) appear to be sufficient to significantly increase bone mineral density and reduce bone resorption.
  • Figure 5: Mean (±SD) reaction time in the high stress–vulnerable (▪) and low stress–vulnerable (□) groups after consumption of a diet containing protein as sodium casein (control diet) and a diet containing α-lactalbumin–enriched whey protein (α-lactalbumin diet | Markus. 2002)
    stress adaptation -- Whey enriched with the protein alpha-lactalbumin has been shown to improve cognitive performance and mood in stress vulnerable subjects (Markus. 2002). Alpha-lactalbumin is particularly high in tryptophan, and the authors proposed that this acts as a substrate to increase serotonin levels, which may be vulnerable to depletion by chronic stress. At the completion of the studies, all of the participants had higher ratios of plasma Tryp-LNAA (the ratio of plasma tryptophan to the sum of the other large neutral amino acids), believed to be an indirect indication of brain serotonin function.

    Recently, de Moura et al. evaluated the effects of whey protein intake on the expression of heat shock protein HSP70 (de Moura. 2013). HSP70 confers cellular tolerance against stressors, and there was a greater increase in the HSP70 expression in the soleus, gastrocnemius, and lungs of the whey protein hydrolysate-fed rats than in the casein-fed rats.
Tsutsumi & Tsutsumi also mention the battle against sarcopenia, where whey is about as useful as it is as a muscle builder in athletes and the support of the gastrointestinal integrity that is mediated by the glutamic acid content of whey which is converted to glutamine and serves as fuel for the intestinal mucosa among the proven health benefits of whey protein, before they conclude their review by stating that we still need studies investigating the mechanisms underlying the effects of whey protein.
Stop protein wheysting!
I have to admit, I am a bit ashamed of how extensively I used the excellent review by Rie and Yasuo M. Tsutsumi when I compiled today's SuppVersity Article. What came out of it, though, is an article with so many facts about the health benefits of whey that I am confident that it contains at least one surprising study result you have not heard of before for each of you... true?

In case it didn't, stay tuned for reports on the future studies investigating the mechanisms underlying the effects of whey protein, Tsutsumi & Tsutsumi demand in the conclusion of their review: I bet you won't have to wait long for the next SuppVersity Whey Protein Article | Comment on Facebook!
  • de Moura, Carolina Soares, et al. "Whey protein hydrolysate enhances the exercise-induced heat shock protein (HSP70) response in rats." Food chemistry 136.3 (2013): 1350-1357.
  • FitzGerald, Richard J., Brian A. Murray, and Daniel J. Walsh. "Hypotensive peptides from milk proteins." The Journal of Nutrition 134.4 (2004): 980S-988S.
  • Hall, W. L., et al. "Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion, and appetite." British Journal of Nutrition 89.02 (2003): 239-248. 
  • Havea, Palatasa, Harjinder Singh, and Lawrence K. Creamer. "Characterization of heat-induced aggregates of β-lactoglobulin, α-lactalbumin and bovine serum albumin in a whey protein concentrate environment." Journal of Dairy Research 68.03 (2001): 483-497.
  • Ikeda, Masanori, et al. "Lactoferrin markedly inhibits hepatitis C virus infection in cultured human hepatocytes." Biochemical and biophysical research communications 245.2 (1998): 549-553. 
  • Markus, C. Rob, Berend Olivier, and Edward HF de Haan. "Whey protein rich in α-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects." The American journal of clinical nutrition 75.6 (2002): 1051-1056.
  • Marshall, Keri N. D. "Therapeutic applications of whey protein." Alternative Medicine Review 9.2 (2004): 136-156.
  • Pal, Sebely, and Vanessa Ellis. "The chronic effects of whey proteins on blood pressure, vascular function, and inflammatory markers in overweight individuals." Obesity 18.7 (2010a): 1354-1359.
  • 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 (2010b): 716-723.
  • Pal, Sebely, Vanessa Ellis, and Suleen Ho. "Acute effects of whey protein isolate on cardiovascular risk factors in overweight, post-menopausal women." Atherosclerosis 212.1 (2010c): 339-344. 
  • Pal, Sebely, and Simone Radavelli‐Bagatini. "The effects of whey protein on cardiometabolic risk factors." Obesity Reviews 14.4 (2013): 324-343.
  • See D, Mason S, Roshan R. "Increased tumor necrosis factor alpha (TNFalpha) and natural killer cell (NK) function using an integrative approach in late stage cancers." Immunol Invest 21 (2002):137-153.
  • Smithers, Geoffrey W. "Whey and whey proteins—from ‘gutter-to-gold’." International Dairy Journal 18.7 (2008): 695-704.
  • Tsutsumi, R., and Y. M. Tsutsumi. "Peptides and proteins in whey and their benefits for human health." Austin J Nutri Food Sci 1.1 (2014): 9.
  • Watanabe, Akiharu, et al. "Nutritional therapy of chronic hepatitis by whey protein (non-heated)." Journal of medicine 31.5-6 (1999): 283-302.
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