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Effect of whey protein on glycemic control (2020)

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INTRO: Welcome to Clinical Nutrition Notes, a podcast where we speak with guest experts and opinion leaders about the art and science of clinical nutrition. Brought to you by Nestlé Health Science Canada. This podcast is intended for healthcare professionals for educational purposes.

I’m your host Cindy Steel, Medical Affairs Manager with Nestlé Health Science.

Today we’ll be speaking with Rachel Adams, to get an understanding of a relatively new concept in protein nutrition, looking specifically at whey protein and the role it can play in the management of blood glucose. Dr. Rachel Adams recently completed her PhD in nutrition at Texas Women’s University. She is a registered dietitian with a Masters of Science degree in nutrition communication from Tuft’s University. Rachel began her career in clinical dietetics, and spent the last 15 years in corporate medical affairs, clinical sciences, nutrition communication and marketing. Currently, she is a health and nutrition communications strategy consultant and an adjunct professor at Texas Women’s University. Dr. Adams has been an invited speaker to medical schools, fellowship programs, and state and national meetings

Steel: Welcome, and thank you for joining us Rachel. You published a review titled Insulinotropic Effects of Whey: Mechanisms of Action, Recent Clinical Trials, and Clinical Applications. To set the stage, can you briefly describe what is meant by the term insulinotropic?

Adams: Sure. The term insulinotropic refers to the ability to stimulate or affect the production of insulin, which is really vital in managing blood glucose levels. Incretin hormones like the gastric inhibitory peptide, better know as GIP, and glucagon-like peptide 1, also know as GLP-1, are both insulinotropic. I was interested in what could be done from a dietary perspective, and specifically in regard to protein choice, to positively affect insulin’s activity.

Steel: Ok. So then as the title of your paper eludes to, it appears whey protein is an insulinotropic nutrient. Can you briefly describe for us, what we know to date about the effects of whey protein on insulin production and action?

Adams: Of course. We know that, in general, whey protein increases insulin production and sensitivity and has a positive effect on the glycemic response. It appears to do this without the negative effect of increased fat deposition, which is often seen with elevated insulin levels or also know as hyperinsulinemia. The benefits begin with a dose of whey protein that can be as low as 10 grams, though most of the research published shows that the best results are really between 25-55 gram margin. Positive effects have been found when whey was consumed as a preload or with a meal. And, the effect of whey preloads was actually strong enough that a couple of different studies have suggested that it be considered a long-term management strategy in patients with Type 2 Diabetes.

Steel: And I’m sure it’s hard to do this without a white board or slides in front of you, but hearing that begs the question, how does whey protein exert it’s insulinotropic effects or action?

Adams: Yes, it’s much easier to describe this one if we had a screen in front of us. An answer to that question is rather complicated and honestly, researchers are still trying to understand exactly how whey exerts it’s insulinotropic effect. But most likely there are a few mechanisms involved and the pathways are all sort of interconnected. This is where a white board would be fantastic. But the three main mechanisms seem to be the comparatively rapid gastric emptying rate of whey protein, second, its effect on incretin hormones, and then third, its ability to inhibit Dipeptidyl peptidase-4, which is quite the mouthful, so I’m just going to refer to it by it’s acronym going forward DPP-IV. So GLP-1 and GIP that I mentioned earlier are incretin hormones with really strong insulinotropic effects – though they actually work through different mechanisms. The effect of whey on these hormones is actually pretty inconsistent in the literature, but that’s probably just because of methodological differences between the various studies. So depending on the study, the dose of the protein, the fat composition of the meals, and the type of whey can actually all affect the response. Whey also digests more quickly than casein, which makes sense if you know much about cheese making. Whey is the liquid portion of milk that’s left over from the cheese making process and the casein is what forms the curds. Some studies have classified whey as what’s called a “rapid release” protein because it’s metabolized quickly. This rapid digestion also causes a rapid rise in amino acids, and specifically the branched chain amino acids, which interestingly are second only to glucose in promoting insulin secretion. The rate of gastric emptying and incretin hormone release have a combined effect, because gastric emptying influences the rate of incretin hormone secretion. Now, besides the effect on gastric emptying and incretin hormones, whey inhibits the action of again, that DPP-IV, which quickly breaks down GIP and is responsible for over 95% of the break down and inactivation of GLP-1. DPP-IV activity is known to be positively associated with hyperglycemia and it is also found that it’s really high in individuals with both Type 1 and 2 diabetes. There are several studies that have also evaluated whey as an adjunctive therapy to gliptins, a group of medications that are given orally that inhibit DPP-IV and are used to treat Type 2 diabetes by lowering fasting and also that post-prandial blood glucose, as well as another medication, metformin – that’s commonly prescribed for the treatment of type 2 diabetes and found that whey can actually lead to an improved glycemic response when used in combination with these 2 medications. Like I said at the beginning, there really is a lot at play here, and it’s a pretty complicated process that we’re still really trying to understand.

Steel: You’re right! It is complicated, and I’m really glad that there’s people like you that have sifted through that literature, and the literature with inconsistent findings to sort it out, and put it as easily as you can in terms that make it understandable, so thank you for that. If whey can do this, is there evidence that shows that other sources of protein, you mentioned casein, have the same effect on insulinemia?

Adams: So that’s a really good question, and most proteins have do some glycemic effect when they’re taken either as a preload or with a meal. However, most studies comparing the glycemic response of various protein sources, which include meals with mixed proteins or vegetarian protein exclusively, these generally report a greater effect from whey protein. Intervention studies have pretty consistently shown that dairy products, including both casein and whey, do have a more potent effect on insulin compared to other commonly consumed animal or plant-based proteins. Casein has been shown in in-vitro studies and mouse models to actually also inhibit DPP-IV to some extent. There was a study published not too long ago by Bohl and colleagues, and found that casein increased the postprandial GLP-1 response compared to whey protein. This is in obese adults, and they were given 60 grams of whey, which is quite a lot, or casein protein with 65 grams of milk fat with either high or low medium-chain saturated fatty acids, and they went on for 12 weeks. Now what was really interesting that despite increased GLP-1 in the casein-supplemented group, there was not a significant difference in postprandial glucose or insulin levels. The GIP, gastric inhibitory peptide secretion was actually not significantly different between the two proteins. The effect of the whey on the incretin response, in this case, was probably blunted due to that really high fat content of the test meal, because we know that high levels of fat will actually slow the gastric emptying and we go back up to thinking about the mechanisms of action would certainly have had an effect on the whey. There was another randomized study on elderly patients to hydrolyzed whey or casein formulas to assess the effect of these proteins on the acute phase response after an ischemic stroke. They found that there wasn’t a significant difference on days 1 or 5, but, in my opinion, there was, what we consider to be a clinically relevant response to the whey since glucose actually only increased from 132 mg/dL on day 1 to 139 mg/dL on day 5, so a 7 point increase between days 1 and 5. But the casein group increased from 148 baseline, mg/dL on day 1 to 214 on day 5. So the body of evidence I think supports a stronger insulinotropic effect and really a stronger glycemic effect for whey.

Steel: Thank you for that. I don’t think I’d like to be a subject in that study where they consumed all of that milk fat, that doesn’t seem like something I would have liked to have been involved with. It certainly helps us tease out what the action is here for sure. So you mentioned this fast gastric emptying, is there anything else about the whey or casein that might have them behave differently, or have different effects on insulin and glucose levels other than that gastric emptying?

Adams: Yes, they are really going back to those mechanisms of action. The answer here is likely multifactorial, and certainly gastric emptying plays a role and the subsequent rate of digestion likely plays a significant role. We know that the branched chain amino acids and bioactive peptides that are found in whey are likely key contributors here. Whey is also known to be more bioavailable. So that basically means that it can have a higher protein efficiency ratio, net protein ratio and true digestibility when it was compared to either casein or a casein/whey blend.

Steel: You mentioned in the previous question, you talked about hydrolyzed whey. We do hear that hydrolyzed whey can empty faster, I believe, you can clarify that for me, than intact whey. Do we see that hydrolyzed whey exerts a different insulinotropic effect than intact, or is it the same?

Adams: So actually, the form of whey protein really does makes a difference, and it seems like for most of the studies that hydrolyzed whey protein and actually casein, when both of them are hydrolyzed, they do have a greater effect. There was a study by Calbet & Holst that found that both hydrolyzed whey and casein elicited about 50% more gastric secretions and greater GIP release than their whole-protein counterparts. This was during the first 20 minutes of gastric emptying after subjects had been fed a test formula through a nasogastric tube. Now as to why you might see this effect with hydrolysis. For whey in particular, now getting back to the branched chain amino acids in whey that are known to stimulate insulin secretion. What’s interesting that with whey though, we know it’s not just amino acids, because some studies point to actually the whey peptides as having a more direct effect. We know that certain amino acids, certainly these branched chain amino acids, and certain types of these whey peptides actually activate the release of incretin hormones when they are digested in the intestine. Also, the type of protease used to hydrolyze the proteins also affects the degree to which DPP-IV is inhibited. There was some research that had shown that trypsin, a type of protease, seems to be the most effective, because peptides that were the result of a trypsin hydrolysis were actually shown to decrease that DPP-IV in a dose dependent manner and also were shown to lower blood glucose. So hydrolysis definitely makes a difference.

Steel: It’s really interesting, and it’s interesting because it’s something that when I was doing clinical nutrition, we really didn’t know very much about at all. To the best of your knowledge, do you know if clinicians are using this information about whey and the impact that it can have on blood glucose management, to help manage patients?

Adams: Yes, kind of like you, I’ve been out of the clinical practice for a while, and thick and heavy in research these recent years. But I do know that there are a couple of practice-based publications that have come out comparing hydrolyzed whey tube feeding formulas to either casein-based or hydrolyzed casein and whey blend in two different study populations – one of them was looking at patients with Type 2 diabetes and the other was looking at critically ill patients who were on the vent. While the formulations varied in both of these trials, both of them demonstrated that patients who were on that 100% whey formula did have significantly improved glycemic responses.

Steel: And that was the two populations of ICU and Type 2 diabetes?

Adams: Correct.

Steel: That’s interesting. You know, in your opinion, where should the research go next, as far as supporting using whey protein to help manage blood glucose? Where would you like to see this, what questions are still unanswered for you?

Adams: So there are couple of places that I’d like to see the research go. Certainly, one is more in place of the hypocaloric feedings, which are becoming a thing. One of the studies I just mentioned was by Todd Rice and colleagues and he was looking at the ventilated population and they use a formula that was novel, in that it was both high in protein, and had reduced carbs, and so that carbs were just replaced with other nutrients. He attributed their findings, which was a lower incidence of hyper-glycemic episodes, an increase in blood glucose levels within that normal range in these patients, to 2 things. One of them being the decreased carbs, and the other one being the effect of whey protein. Whey protein was kind of a passing mention, but I feel like given what we’ve just been discussing today, there’s probably a lot there and that it probably does play a pretty significant role. Treating these critically ill patients is an area of great interest and opportunity. Another one is, I think is probably the most interesting effective result of whey on insulin is that while it increases insulin production it has not been found to increase fat mass. I mentioned that briefly when I talked about fat deposition, but hyperinsulinemia is typically linked to obesity and we don’t yet know why increased levels of insulin resulting from this whey don’t have this effect. I think it’s pretty underappreciated and actually deserves more attention. In fact, whey has been shown to have the opposite effect of what you would expect. Recently published studies on people with type 2 diabetes who were supplemented with whey, and they found that even small doses of whey, I’m talking considerable small doses, 15 g as a preload, lead to significant improvements in satiety, in men with Type 2 diabetes and then the patients experienced significant weight loss, with Type 2 diabetes while on these preloads. So I think there’s a lot there to look at in terms of satiety and weight control to explore with the whey protein.

Steel: Yes, I think you’re right. Certainly an area where a lot to learn, a lot to understand. I know that I will go back and listen to this many, many times to understand the mechanisms, and I really appreciate you taking the time with us today to summarize it and try to make it a topic that’s understandable and to generate some interest. Because until we have interest we won’t have people asking the questions. I really appreciate that. We’d love to end the podcast with a question that we ask all of our guests and so that our listeners can get to know you a little more. Can you tell us how you first became interested in the field of nutrition?

Adams: Well, it’s sort of an interesting response given our topic. I actually grew up on a dairy farm in Texas, and in case of full disclosure because we were talking about whey, I feel I need to tell your listeners that I don’t take any funding from the dairy industry, which is sort of interesting that I ended up researching whey. Both sets of my grandparents lived nearby and they both had gardens that were over two acres. They were these huge beautiful gardens. It was really, for a kid growing up in Texas, in the country, it was pretty idyllic to have such great family close by. One of my grandmothers would make sourdough bread a couple of times a week and she would tell me how she added wheat flour and oats to increase fibre and raisins for iron. My interest in nutrition started when I was really young, and it grew as I became involved in 4H, a leadership organization for kids, and then, when I was in school, I became more interested, and through high school. I saw my grandfather actually pass away, I think, way too young, because of heart disease and complications of diabetes, and it was really then that I began for the first time to become interested in nutrition from a medical perspective. That’s what led to my undergraduate degree in nutrition, then after that, I became less interested in the clinical work and more interested in the research and communications. Part of this is just from growing up on a dairy and having exposure to the food business and so I did a Masters in Nutrition Communication because the one thing I know for sure about this field is that not only does everyone have an opinion, but everyone seems to think theirs is an expert opinion. I actually just finished my PhD in nutrition because I wanted to understand the science better in order really to communicate it more effectively. I believe it is so important that, as nutrition experts, we do our very best to help consumers and patients make informed choices about the foods they eat that can impact their health and the role nutrition can play in disease prevention and management.

Steel: Key things for sure. And we’re glad you did do your PhD and carrying on and helping us understand this. On that note, I’d like to thank Dr. Rachel Adams for joining us and for shedding some light on another example of how there is still so much more to learn about nutrition and the role that specific nutrients, as well as foods as a whole, can play in the management of health. Thank you to all of our listeners.