Lowering Blood Sugar Without Weight Loss | Dr Nicola Guess

0:03You've done a lot of work on what's described as calorie-independent dietary approaches to type 2 diabetes. And I read a review, a kind of framework that you put forward in 2022 on this. And then I saw that that thesis has been sort of since supported by other groups and people that have shown that pre-diabetes remission is possible without weight loss. for example, and this is where I want to start our conversation today, why have calorie-independent approaches to managing type 2 diabetes and preventing type 2 diabetes perhaps been such a focus of your research? It really comes from patient-centered, is what patients have told me.

0:50So I am an academic researcher, but I do that part-time, but I also see patients and what became abundantly clear seven eight years ago when remission started being possible it started being a thing that really captured the imagination of patients patients with type 2 diabetes they want remission and if they can't achieve complete remission they at least want to come off their meds but to achieve that you're talking 10 kilograms of weight loss for lots of people they don't want to do that it might not be clinically appropriate for them So that's what I was hearing from patients. And I thought to myself, well, what can I do as a dietitian to help this become a reality?

1:28So I began a series of studies which manipulated carbohydrate and protein concentrations, keeping weight constant, keeping calorie constant to see if we can improve glucose. and so what that has shown and this is confirmed by others research is that if you have type 2 diabetes and you follow a high protein low carbohydrate diet by high protein i'm talking 30 percent of calories from protein so it's quite a lot you can lower your glucose by more than medications so postprandial glucose in some of the studies come down by four millimole per liter I can't do the maths in my head, but it's about 75 milligram per deciliter.

2:08Huge, without weight loss. So this is really exciting. And I've actually recently got funding from NIHR, who are a big funder here in the UK, to develop a program actually for patients. And the idea is, like the largest group of people with type 2 diabetes are the over 60, over 65 year olds. They don't want to lose 10 kilograms. So the idea is with this diet, we can help people improve their diabetes without having to lose weight. Right. And we're hopefully going to get into the specifics of that and what that looks like in practice for an individual as this episode unfolds. You alluded to the fact there that the last 10 years, there's been a lot of research looking at remission and the possibility of remission.

2:52So has this been a big paradigm shift in diabetes care? So before that, was there a time where once you were diagnosed with prediabetes or type 2 diabetes, people thought that was it? you just had that for the rest of your life and you'd go on medications and potentially deal with the complications as they come up? 100%. When I was a dietician back in 2008 in the NHS, I mean, you would just manage it. So you would give advice to reduce risk factors to the extent that you could. But the idea that your job as a dietician was to help people come off medication just wasn't anything that entered my head.

3:30And then we had the bariatric surgery data that showed actually people could get remission of type 2. The question then became, is it weight loss? Is it something else? So it all came from there, but 100%. I think though, I would say, you know, we need to be really careful with how we define things and the words we use. Remission is a really good way of describing it because it means you don't have diabetes at the present time, but it could come back. And I think we do need to be very honest with patients about the durability of remission. It does involve, for lots of people, significant weight loss and maintenance of that weight loss, which is really tough.

4:07But there are some people that have achieved remission and they still don't have diabetes based on a hemoglobin A1C test now. Is there a formal definition of what remission actually means? We do have one and it will probably change. I mean, they're all glycemic, which is understandable, but it's interesting. So basically, it used to be if you had a normal A1C, actually, it's not even normal. It's just under 48 millimole per mole. So if you had a non-diabetic A1C and you weren't on medications, that was remission. Some people say you can be on metformin and they call that partial remission. Now, the official ADA, ESD definition is that your A1C has to be less than 48, at least three months, on two occasions, three months apart without medications.

4:51Is that a narrow definition given the kind of complexity of type 2 diabetes, the pathophysiology? A hundred percent. So historically, type 2 diabetes has been very glucocentric. The name is based on glucose. We define it by glucose. We diagnose it by glucose because we didn't understand what was going on underneath. And what's become apparent is that type 2 diabetes possibly could be better thought of as a disorder of fat metabolism. It's probably fat-derived insulin resistance and organ crosstalk that's causing it. So it's not just glucose which is causing the complications of type 2 diabetes.

5:31In fact, what's striking, and this is new data that has changed what we think in terms of caring for people with type 2 diabetes, is that even if you lower glucose, it doesn't necessarily prevent heart attacks or strokes. So now let's think about this from the context of remission. Just normalising your glucose alone is not a guarantee that you're not going to get any of the complications of type 2. Lipids, LDL cholesterol is critical, as is blood pressure. So the point you made, is that a narrow definition of remission? It is, because ultimately what you really care about when you look after someone with type 2 diabetes is heart attack, strokes and preventing microvascular complications too.

6:11Which fades into my next question. If we use that narrow definition of remission, do we understand what's up for grabs for someone? Let's say, for example, someone's listening right now, they have type 2 diabetes, and let's say they're taking a couple of medications, and they're managing their blood glucose fairly well. If they were to implement some of these changes, be it, let's say, calorie restriction, some of these dietary manipulations we're going to talk about, and they're able to meet this definition of remission and restore blood glucose control and reduce or come off of medications, have we shown that that leads to better long-term outcomes?

6:53100 % improving glucose reduces microvascular complications. So in type 2 diabetes, you get two primary, there's even more, but we'll stick with the two primary, macrovascular complications. That's diseases of the large blood vessels. We can think of this as being like heart attacks and strokes. Then you have microvascular, that's disease of the small blood vessels. So that's conditions of the eye, of the kidneys, that relates to amputation, for example. Now, if you improve your blood glucose, you can definitely reduce your microvascular complications. That is abundantly clear. what is less clear and the data is a lot murkier is whether lowering glucose does anything for macrovascular complications so you definitely if you have diabetes and i know we're going to talk about glucose a lot in this conversation glucose is directly harmful only in diabetes so i want to make that abundantly clear that no one misinterprets what i'm saying by thinking oh i've got pre-diabetes or and i have a glucose excursion after a meal that looks high we are talking about diabetic levels of glucose.

7:58That if you have diabetic levels sustained, your fasting is above seven millimole per liter, your A1C is above 48, your two-hour glucose is above 11 millimole per liter. That, if you reduce it, prevents microvascular complications. That's a really important point because often that nuance is lost, particularly in the wellness sphere where, yes, someone with type 2 diabetes can have downstream complications of these large glucose excursions and poor management, as it might be described. But that's not to say that glucose going up and down cannot be a part of normal physiology. Yeah, it's the dose and the duration of exposure to that dose that matters here.

8:41And right now, there's no data that glucose is directly harmful if you don't have diabetes. A term in the wellness world that I think is really popularized in the last decade is metabolic health. And I'm wondering, as a researcher and a clinician, how do you think about that term, metabolic health, and what that means and where type 2 diabetes and some of these other conditions kind of sit within that definition? Metabolic health, I kind of link it with cardiometabolic health. I mean, if you're metabolically unhealthy, you're probably going to be at risk of cardiac-related conditions. So when I think about metabolically healthy, I think about the organs working properly.

9:29So your metabolism, for example, primary manager of your metabolism is liver. So when I think about metabolic health, I think of someone whose liver is functioning optimally. Their muscles are very insulin sensitive, so they are probably an active person. So I think to me it's about optimal organ function. That's how I think about metabolic health. It's not just the things that we can see, taste, smell, or feel that shape our health. Some things slip by completely undetected. BPA from plastics and receipts. PIFAs from clothing. Yes, your favorite activewear. Mercury from fish. These are just a few of the everyday items that contain compounds linked to hormone disruption, cognitive decline, and illness.

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10:59With Function, I get a clear read on where I actually stand today. Check your health the way that I do. Function provides 160 plus lab tests for just$1 a day and member pricing on advanced imaging. Join at functionhealth.com forward slash Simon Hill and use the code Simon 25 for a$25 credit. So if you take steps to look after the health of your liver and the health of skeletal muscle, that goes a long way to preventing conditions like prediabetes type 2 diabetes, muscle D, etc. Yes. And what is the distinction there that separates, let's stay with the liver for a moment here. Would it be accurate to say that the liver plays a crucial role in the development of type 2 diabetes?

11:52I don't know to what extent it's causal, because it's very difficult to study. And I'm sure you're aware and you've spoken to people before about the idea with remission, we see fat disappearing from the liver. And I think there is an assumption that that is part of type 2 diabetes. It's definitely linked. But my interpretation, like you can have elevated liver fat if you don't have type 2 diabetes. You can have really marked insulin resistance without type 2 diabetes. They all come together. And primarily, it is obesity, calorie excess, sedentary lifestyle that leads to fat being deposited in excess and being deposited internally, including to the liver.

12:33So it's definitely linked to metabolic dysfunction. We have some preclinical studies where you do see crosstalk between the liver and the pancreas, and that's another important organ in metabolic health. So there's a link there, but I don't know at this point whether anyone understands how causal that is. What is very, very clear is that weight gain will lead to depositing fat in the liver and probably the pancreas, and weight loss does too. But throw Roy Taylor at me because he's the man. So tell me what Roy said to you. I've asked a bunch of people this. What is it that increases someone's probability or propensity to store fat in the liver and in the pancreas at a certain level of total body fat compared to the next person who seems to be somewhat protected against that and might be the same overall body fatness, but doesn't have the same amount, degree of insulin resistance, and doesn't get the diagnosis of type 2 diabetes.

13:34I thought you were going to tell me what Roy said. I mean, I can give you my thoughts. I don't think we know entirely. There is some genetics, and this is becoming more interesting now we are getting better at doing genetic studies. There was a really nice paper published, I think she's now at the University of Leicester, Hania, who does genetics and body composition. So she was looking at biobank data, which has really perfect measures using MR of pancreatic, liver fat, intra-abdominal, subcutaneous. And it is clear that there is genetics driving where people deposit that fat. And unsurprisingly, the people that were able to deposit that fat in subcutaneous tissue were much better off than people who deposited it around the middle.

14:19So as visceral fat, liver fat, you name it. So genetics plays a big part. I do think there is some data for nutrition playing a role. And I'm sure we'll talk about this one thing proteins do and amino acids do. And this is so unpopular as an opinion, but this is what the data shows, protects fat deposition in the liver. Because everyone freaks out about high protein or if you're not having protein, or if you're having protein, you're not going to have fiber, but there is really good trial data that protein and amino acids lowers liver fat, but also protects the liver from fat deposition in overfeeding trials.

14:54So that's something that is an independent mediator, as is physical activity, probably a lot of viscous fiber as well. Yeah, that was a similar response to Roy Taylor and everyone else. Okay, that feels good. If someone's listening, sitting here and thinking, I haven't been diagnosed with type 2 diabetes or Masl-D, so therefore I must be protected against these. If you don't have a diagnosis, does the absence of the disease mean that you are metabolically healthy? Oh, that is such a tough question to answer. I mean, I would answer that like a clinician. I mean, I just look at the measures that people would have done and largely we do those measures in clinical practice in the NHS because there's good evidence behind them.

15:42So what I look at is waist circumference, blood pressure, LDL, cholesterol. You do a clinical history. Being physically active is important because if you're not, you're going to be metabolically healthy sometime in the near future. Resting heart rates are a good measure of how aerobically fit someone is. That's a good indicator of whether they're metabolically healthy. What I'm hearing is that if you don't have a diagnosis, then you still want to be doing routine checks with your physician, whether that's once a year or whatever it is, and blood work, and looking at some of these important markers like LDL cholesterol, presumably the blood glucose ones like HbA1c and fasting blood glucose as well.

16:23Yeah. In most people, A1c will do the job, yeah. Yeah. And then waist circumference, blood pressure. And if you're kind of ticking the boxes on all of those things and you're in the healthy range for your level, then you probably are metabolically healthy. Yeah. And I would say if there's a single one of those that's probably the most important, it's probably waist circumference. I mean, because that's going to tell you, we talk about the limitations of BMI, but if someone's got a large waist circumference, they are depositing fat likely in the places where it is going to, at some point, lead to metabolic dysfunction.

16:59Before we get into the nutrition strategies, if we just linger a little bit more on the mechanism and how type 2 diabetes develops, and you sort of walked us through so far that in your view, and this is consistent with what I see in the literature, is that there's typically an energy excess component. And at some point in time, and Roy Taylor describes this as a personal fat threshold, some people can gain a little more fat than others, but when that fat starts showing up in places where it shouldn't be, like the liver and the pancreas, it can lead to some of these downstream metabolic repercussions that we're talking about.

17:45And yet there are some people out there that have a different view. And I know that you've written review, I believe, on this. If someone like Ben Bickman, for example, was sitting here, he might say that actually it's not the increased energy that precedes this fat deposition and sort of lipotoxicity. it's that insulin resistance is the kind of starting factor or ground zero that someone is first insulin resistant and as a result of that increased insulin that then drives obesity what's your kind of view on that as you sit here today whether insulin or weight gain comes first is actually really really difficult to study because if they happen to get like one happened shortly after the other how can you pick it up we do have studies where they overfeed people so they give people too many calories and they measure different aspects of metabolism over subsequent days.

18:43And what that data shows, if you overfeed calories, you overwhelm the body very, very quickly. So you see in the short term a rise in fasting insulin before you see any change in weight. So that to me is direct evidence that it is calorie excess causing one of the contributors to developing insulin resistance. So I don't buy, I don't think there is evidence that insulin resistance itself is the primary causal factor in the development of type 2 diabetes. There is other evidence, and again, let me iterate how hard this is to study, but even if you do cross-sectional studies on people who don't have diabetes yet, for example, and you look at their insulin response to glucose, you look at their hepatic insulin resistance and their peripheral insulin resistance, you can see defective insulin secretion before you see any changes in insulin sensitivity at all.

19:41So it might differ between people, but the fact that if you overfeed people and you cause them to gain weight, their insulin goes up, like their fasting insulin goes up, and they get insulin resistance. Then if you have people lose weight and reduce their calories, both of those things. So let me reiterate that they are independent. The calorie reduction, itself, even before weight loss starts improving metabolism and weight loss will reduce fasting insulin. So that I think in the vast majority of people is what's happening. It is calorie excess and weight gain leading to perturbations in metabolism against a genetic or epigenetic background of susceptibility.

20:24You kind of sit in this interesting place where even though from my observations and what you've just explained there, you have a different view and way of explaining the physiology of type 2 diabetes to someone like Ben Bigman. But where you, it seems like you all, you agree in terms of the intervention, at least to a degree, that low-carb diets can be a good strategy for managing pre-diabetes and type 2 diabetes. Whereas there's this whole other world of people out there that are really more of the view or promoting low-fat, high-carb diets for people with type 2 diabetes? I think I would add some nuance there.

21:02So again, let me separate pre-diabetes and type 2. And the reason I do is because glucose is directly harmful in type 2 diabetes. It's high enough to cause damage. Therefore, you want to fix the glucose. But in both those conditions, in pre-diabetes and type 2, the level of hyperglycemia, the fact that you have hyperglycemia is driven by the fact you have insulin resistance and beta cells that don't work properly. So pre-diabetes is the same physiology, it's just early. So in both those conditions, ideally you want to fix the underlying physiology. So that's the same. But where I make a distinction in type 2 is that you do actually immediately want to lower the glucose.

21:40So I think low carb is great for type 2 diabetes, but my interpretation of the data is that it's because it's high protein. that is what I would describe as being physiologically optimal and the reason is that in type 2 diabetes the beta cells that sense glucose don't work properly so the reason you get a poor insulin response to carbohydrate or to a meal in type 2 diabetes is the beta cell sensor's job is to detect glucose doesn't work so if you've got type 2 diabetes and you have a bowl of cereal, your glucose goes up, but your pancreas has no idea because the sensor's not working. But there are amino acid sensors and they still work in type 2 diabetes.

22:26So if you have type 2 diabetes and you have a meal that's high protein, it's a signal to your pancreas, oh, someone's had a meal. Let me produce enough insulin. And that's what helps bring glucose down. So the amino acid sensors sit within the beta cells and those are still functional? Yeah. So we separate glucose-stimulated insulin secretion. That is the mechanism by which glucose itself goes up, tells the pancreas glucose is going up, you need to produce some insulin. That's how it normally works in healthy people. But there is also amino acid-stimulated insulin secretion. And this is primarily the reason why high-protein diets are physiologically very effective in type 2 diabetes.

23:09Is that different to someone with type 1 diabetes, do they lose both the amino acid receptors and the glucose receptors in the beta cells? Yes. So in type 2 diabetes, it's the sensor. So the way we think about certainly early type 2 diabetes, it's a functional defect. The beta cells are still there, but they're clogged up. It might be inflammatory factors. They might be poisoned by too much glucose or fat. They don't work properly, but they're still there. In type 1 diabetes, they get destroyed by the immune system. So it's completely different. And has that amino acid sensing approach in people with type 2 diabetes, has that been shown in clinical trials?

23:49Or how do we know that? If we infuse amino acids, either intravenously or orally, in humans, with and without type 2 diabetes, you get a marked insulin response. If you take cells, so beta cells, they can either be from cell lines or they can be from cadavers. So you take, sadly, people who've passed away, who've had type 2 diabetes, you take their cells. If you put them into petri dishes and add amino acids, you get insulin secretion. So it's definitely a direct effect. I don't want to But have you been keeping an eye on the stem cell therapy kind of interventions that companies have been doing with type 1 diabetes, where they're growing islet cells and then infusing them?

24:32Vaguely. I know a couple of people doing that work, yeah. But I wouldn't go there just because I know nothing. Like, I'm not a type 1 person. But it's fascinating. Like, everyone talks about the cure for type 1 diabetes. Like, this is pretty exciting. Yeah, I went there in my mind for a second because I wondered if in the future you could do similar with people with type 2 diabetes and restore the beta cell function to get glucose sensing back. I don't think so because depending on the person, but a lot of type 2 again, the main problem is that they've just got, they're consuming too many calories and they've got too many calories as fat stored in the body.

25:12And unless you fix that, you're not going to markedly improve their cardio metabolic fitness. If you just improve the beta cells and you don't improve liver fat or insulin resistance in the muscle, you're fixing 10 % of the problem. Yeah, I was thinking more for the person, and correct me if I'm wrong here, but as I understand it, some people who have had type 2 diabetes for a very long time, if they lose weight, they don't get full restoration of beta cell function. Yeah, maybe, and that's a good point. Yeah, maybe in those people. Do your views or has your views on these calorie independent approaches to type 2 diabetes, have they changed at all with the emergence of GLP-1 medications?

25:55No, not really. because to a certain extent they are targeted for different populations. So GLP-1s, and we'll come on to that, is primarily a weight, it does things metabolically independent of weight perhaps, but primarily it's about reducing weight and by doing so improving cardiometabolic health and type 2 diabetes. The reason I was interested in weight independent ways to improve glucose or improve blood pressure was just because 10 kilograms of weight loss is never going to be right for everyone. And like I would see, I remember some patients in my clinic who were like 72 years old and because they'd heard this thing about, oh, you've got to lose 10 kilograms, remove the fat from your liver.

26:37That's how you get remission. They'd done that. And I'm not kidding when I say some of them looked like starvation victims afterwards. They were so eager to get remission that they reduced their weight beyond a level that was probably healthy. So what it said to me is as the population ages and the group with the highest prevalence of type 2 is the over 65s, that group is going to grow and grow and grow over the next decades. We need ways of helping people to improve their diabetes that don't just rely on weight loss. Even if they lose two, three kilograms, great, it'll improve their metabolic health a bit, but it gets that extra improvement in glucose.

27:14That makes sense. How much improvement do you think someone can get in their glucose by making the changes we're going to walk through with the protein changes, maybe specific types of fats I want to get there, fiber, lowering carbohydrates. If you stack these things on top of each other that you're recommending, what's the magnitude of effect someone could expect? It might be slightly different between people. The biggest impact of high protein, low carb is always going to be on postprandial glucose. But that matters because and people with type 2 diabetes, glucose can get to 17-18 millimole per litre.

27:49That is toxic to the tissues. So you can probably get four, if you don't lose weight, a reduction of about four millimole per litre in post-pranthal glucose with that approach. Whether or not adding additional fibre helps, maybe it does. So if you're going with the high protein, low carb approach, if you try to get that carbohydrate from legumes or high-fibre sources, maybe you get another extra benefit. But where I think the viscous fibre, so again, that's the kind of fibres in oats, in legumes, that seems to help fasting glucose and that's a good thing. Do fibre supplements like psyllium husk help at all?

28:31They do. Primarily, it's post-prandial glucose. It forms like a gel in the stomach contents, which slows glucose absorption. So it does. And with all fibres, it has very subtle effects on the physiology. So we do see improvements in insulin sensitivity in both adipose tissue and in muscle tissue when people have high fibre, like high viscous fibre diets. Where we look at the type of fibres, like in legumes, there are some studies that show it reduces fasting glucose. So it's reducing the glucose coming from the liver, suggesting it's improving liver insulin sensitivity. So yeah, we definitely see very subtle but important benefits with added fiber on the pathophysiology.

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32:11That's code simon at im8health.com to get started. Just to reiterate a point that you made earlier, when you say postprandial, you're saying after someone eats a meal, it can lower their blood glucose. But again, that's only meaningful and impactful if you're coming from a level that is in the unhealthy range down into a healthy range versus the other interpretation of that is just flattened blood glucose in the postprandial period. Yeah, 100%. Because I recommend high protein, low carb diets for people with type 2 diabetes. And people sometimes accuse me of recommending that diet for the whole population or for pre-diabetes.

32:51I don't. Not because I think it's an awful way to eat. It's just unnecessary. Your glucose isn't a problem. So for people who don't have a glucose that reaches a concentration that's toxic, your best bet is to focus on a healthy diet that is going to help improve your underlying physiology. So all the fibres and stuff we talked about. And if someone does have type 2 diabetes, they're hearing what you're saying and they're thinking, okay, I probably should focus a little more on protein. What are the important things to think about when it comes to protein from your research with regards to, is it the amount?

33:27Is it the source? Is it the timing? Or is it other factors that matter most? So with regard to like the type of protein, that doesn't matter to any meaningful extent with the insulin secretion. There are marginal differences if you have a vegan versus meat-based amino acid profile, slight differences, but does it impact the insulin secretory response? No. So whatever your diet is, don't worry about it. If you're getting enough protein, you'll get the rise in amino acids and the insulin secretion. But what I focus on in my practice, of course, is the overall healthiness of the diet. So if I see patients who consume animal products, like having a lean protein, having chicken breast is a really high protein source, But I always encourage, and this is a great way of meeting the target, is by combining a piece of chicken or a piece of fish and a legume.

34:23So whether it's lentils or chickpeas, that way you're probably getting about another eight grams of protein with the legume, but you're getting all of the fibre and goodness that's going to continue to help. And does the timing, a lot has been made on kind of timing and order of things on social media. What I'm hearing from you is that in a sense, protein kind of primes the system for carbohydrates because it is getting these beta cells to produce insulin that otherwise are a little bit sleepy in someone who has type 2 diabetes. So the protein kind of wakes them up. But does the timing relative to say consumption of carbohydrates matter?

35:05Is protein digested slowly and you want to have it at the start of the meal and then have your carbohydrates or is that getting way too complex? It's a really interesting point because you would expect that to matter. It doesn't seem to. So in the studies that have given this high protein, low carb diet, they don't specify the carbohydrate first. We do have studies on protein preloads where people are having it 30 minutes before, 15 minutes before, and it works great. But I just think that's an annoying way to eat. So having the high protein with the carbohydrate, with the meal, however you like it, seems to be perfectly good enough.

35:38I know people will want me to ask this. How do you feel about amino acid supplements then as a kind of way to biohack or hack this system without having to eat a really heavy meal if someone has low appetite, for example? So that's actually something that we're working on at Oxford in some of our studies. We're interested because it is hard to have a high protein diet for lots of people trying to get 30 % of their calories from protein. It's just hard, especially for older people because you might have to chew loads. It can be a difficult thing to achieve. So we were interested and we are interested in whether we can select the particularly insulinogenic amino acids.

36:19By that, I mean the specific amino acids that seem to work together the best to produce a large insulin secretory response. And the reason we think that is probably the case is that amino acids work actually by different mechanisms on the beta cell. So whereas, for example, you have glucose-stimulated insulin secretion, it's just glucose and it just works one way. So when that one way stops working, the beta cell is screwed, as we've seen. But with amino acids, there are 20 of them. And what we think is because they all work differently on different parts of the beta cell, That's what generates this response in a sleepy beta cell.

37:00So what we want to do is try and find the three amino acids that are complementary that can produce a supplement. But that we'll know in 10 years. But I think it's a valid point. Is this the concept, science, about sort of protein priming, people with type 2 diabetes, is this generally accepted by your peers and colleagues in the ADA, for example? Or is this something that we would expect to see in their guidelines? One of the tragic things about dietary guidelines, and I think I disagree with it, is that they only select certain study designs in trials. So it has to be usually longer than six or 12 months.

37:41They're usually free living. What does that mean? That means that no one's following the diet that they actually test. So what you find is the guidelines are really, really inconclusive. and I understand why they are because they say it's not high quality evidence. As a practicing dietician though, what informs my practice is carefully controlled trials where we know what people are doing because that enables us to actually test a hypothesis. If you are interested in whether a low carb diet or a vegan diet or whatever it might be improves glucose, you have to follow people who are following that diet.

38:20It's useless if no one's following low carb by three months. All it tells you is that this is a tough diet to follow. So, and I've never seen a patient in my life who wanted to know what the result was from a 12-month trial in which no one was following the diet that was suggested. What does it mean to a patient? Whereas a patient, what you want to know is, if I do X, what will happen? So in answer to your question, the dietary guidelines don't recommend high protein diets for type 2 diabetes, because the trials that are really well controlled are five to six weeks long. The longest is probably 10 weeks.

39:02But this is what my research is looking at. So as part of my funding, we're doing a feasibility trial with 150 people, we're going to follow them up for longer and then do a proper trial with it. Interesting. Well, you'll have to keep us posted on that and come back and share when the results are available. Okay. So that's protein. What about fat? Does the amount of fat that's in our diet or the type, be it saturated, which again is an umbrella term, there are different types, monounsaturated polyunsaturated do these things matter in terms of beta cell function secretion of insulin i know i've come across some research that suggests independent of calories perhaps the type of fat affects liver fat and insulin resistance in the liver do you have any thoughts on this yeah so they seem to so if you and it's about replacement if you replace the typical saturated fats in the diet, like the unhealthy ones in butter, and you replace them with polyunsaturated fat.

40:08There's pretty good control data showing it reduces internal fat and liver fat. The effect is small, but it's there, it's significant. There's some interesting data on monounsaturated fat. In fact, there are meta-analyses showing that monounsaturated fat seems to reduce fasting glucose. And in some pretty well-controlled ward-based studies, a low-carbohydrate diet that isn't high in protein but has loads of monounsaturated fat lowers glucose. So I can accept maybe there is a signal that PUFAs and particularly MUFAs might be doing something to glucose. Then of course, we have the PREDIMED study where they found that this diet, the Mediterranean diet supplemented with either nuts, seeds or olive oil help prevent type 2 diabetes, even though people didn't lose a significant amount of weight.

41:03So yes, I think that although the effect is probably small, the type of fat and the quality of the fat probably help prevent type 2 diabetes. Just about to bring up the Mediterranean diet because it seems very consistent with all of these individual recommendations you're making, perhaps with a little bit more of an emphasis on protein. But that dietary pattern kind of ticks the boxes when it comes to the type of fat that you're talking about. It includes fiber and you can make it higher or lower in protein. Yeah. I mean, whenever I think about the Mediterranean diet, very healthy. In the UK, it's probably going to be expensive.

41:42I think it's almost more useful just to think about healthy dietary patterns in terms of lean protein, lots of whole fruits and veg, whole plants, whatever, you know, nuts, seeds, whatever it looks like, healthy fat. It might not be olive oil, but like if we look at, for example, at like Japanese societies who don't have olive oil, they live for a long time. So it's not clearly a necessary ingredient. But I think that lean protein, high fiber, high plant based, those are the elements I think are the most important that we should be focusing on. And what about someone with type 2 diabetes? What about foods like fruit that contain fructose?

42:24More fructose than other foods. There are some researchers out there that appear to be very worried about fructose and liver fat and insulin resistance. What are your views on that? With whole fruit, it's irrelevant. I mean, the only time I have patients who follow a very strict low-carb diet because it really works for them. They love it. That's what they want to stick to. They are the only people in whom I would even mention fruit because they always have that question. And if they ask it, there are low carbohydrate, low sugar fruits that you can have, or I'd just recommend have it at the end of the meal and you will absorb so little of the glucose and it will be absorbed so slowly it's not going to impact your glucose.

43:04I never, ever care about whole fruit. Unless someone has an allergy, the idea that anyone needs to be worried or avoiding whole throat is just madness. And in practice, when you are working with a patient who has these goals, what we're talking about, let's say putting their type 2 diabetes into remission, you're giving them all of this advice. They go away into the real world. I'm assuming also their physician is aware of this. And are you kind of along with their physician just monitoring those biomarkers and different measurements that we mentioned earlier to see whether they're normalizing, whether medications are changing?

43:42It depends on the patient. So I see patients privately and sometimes they do and don't have a good relationship with their primary care physician. Others might see an endocrinologist, but I do see actually others who are very much, they're really into monitoring. I worry about over-monitoring and over-measuring because I think it can take over your life. But I did have a patient, for example, who had elevated liver fat. Interestingly, he was vegan and he was vegan on a very, very unhealthy vegan diet and with probably less than 10 grams of protein a day. So I suggested to him, try and increase your protein, you know, plant-based meat alternatives and all of that, that reduced liver fat.

44:22So he did actually go and get followed up with an MR. And just by increasing protein into a vegan diet, he reduced liver fat. So I think it can be helpful. But for most people, I mean, again, it's like waist circumference is for the majority of people, they're going to have some overweight or obesity. And the improvement in waist circumference is going to be the signal that tells you everything else is improving. And are you seeing some people come in on multiple blood glucose medications and eventually they're in a position where they don't need anything? Yeah, that can be really common. It depends.

44:56I mean, again, let me be realistic. For lots of patients, they can come off their medications. For lots of patients, they can reduce from three to one. Some people have to stay on one and that's okay. So for example, like metformin is a great medication. Very, very safe, decades-long safety profile. If that's what it takes to keep people's fasting glucose in a healthy range, great. But they can come off insulin. They can come off their other meds. So yeah, that's very common and very achievable. Do you give any recommendations around the timing of meals, how many hours across the day someone's eating and sort of when they're moving their body, does moving their body after eating a meal or before, does any of this really make a difference in terms of blood glucose homeostasis?

45:40Not significantly, and it's not worth the attention paid to it, like to focus on something like that for the gains that you might get. I do think timing can be helpful behaviorally. So I think as a behavioral tool for some people, if they have this idea, okay, I'm not going to eat until 11am or I want to do intermittent fasting, I think as a behavioral tool, that can be useful. But I wouldn't do it for benefits on metabolism. The gain is not worth the effect on your life, I think. Is there any issue with eating right up until bedtime? I think the main issue with it is the impact on someone's sleep, that they just wouldn't sleep comfortably or well.

46:20And it's the sleep deprivation or inadequate sleep that then affects appetite, insulin sensitivity the next day. There is some data that if you have too many refined carbohydrates late at night, you know, as a proportion of calories, that impairs blood pressure and all glucose homeostasis to a certain extent. But, you know, one of the reasons I caution about overinterpreting this data is like eating a lot of your calories late. The effect size isn't huge. But what I also see, like, so I eat late, but I eat late because I go to the gym late. I like exercise to be one of the last things I do in the day.

46:55Like I run off my day, I go to the gym. So I eat late because of that. And that's useful for me to refuel. And I see patients who are like this too. They have a busy day. They're doing weight training, muscle strengthening exercises, and they want to eat afterwards. And then they start worrying about this. And like, I don't know if there's any data on this, but I would die of shock that metabolically going to the gym and having a large meal at 10pm was bad when you'd just done the exercise. And quick word on eight sleep. Here's a fact that I certainly didn't know. Women weren't required to be included in federally funded US research until 1993.

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48:51Relatively compared to the other things we're talking about, like if someone is overweight and has excessive fat in their liver, losing weight, and then some of those different calorie-independent dietary strategies, you're saying those are going to shift the needle a lot more. And they're a lot more flexible in the way that people can adapt them into their lives. A big chunk of my audience is women over 50. And many of them have noticed that through perimenopause and into menopause, their metabolic health has shifted. And perhaps some of those those biomarkers we spoke about before. Maybe they were in the normal range for most of their life.

49:29And then with their latest blood test, things seem to have changed. Perhaps they got a new diagnosis. And often they report having more body fat around the midsection. What is, in your view, driving these changes in kind of metabolic health and how a woman in her 50s might be feeling? And are there different strategies that you have for this population or are they paying attention to the same things we've already gone through? Great question. I'll answer the latter one first. No, there's not different advice. So the same advice about body composition and about being metabolically healthy is the same for menopausal women, postmenopausal or men.

50:13It is true that hormonal changes are driving changes in glucose metabolism. So for example, one of the things that's kind of interesting we see with pre-diabetes, that's when your blood sugar is slightly high, but not high enough to be type 2. And when you have pre-diabetes, your glucose can either be high in the fasting state, that's the liver, liver insulin resistance, or postprandially, postprandial. So some people have elevated fasting, normal postprandial. Some people have elevated postprandial and normal fasting. Men are more likely to have the former. They are more likely to have liver dysfunction, elevated fasting glucose, but normal postprandial.

50:54Women are more likely to have elevated postprandial and normal fasting. After the menopause, that changes. Women develop more of a male glucose phenotype. So it's their fasting glucose starts creeping up. And what's interesting is there are some studies where you give HRT, so you're restoring those female protective hormones And again, it reverts back to this female pattern of glucose tolerance. So there's definitely something going on, which is interesting for me as a scientist. Does it matter for someone who's got weird glucose? No. Exactly the same advice applies. Another condition I wanted to run past you, which I believe has a metabolic component, is PCOS.

51:35Arguably gets less airtime than type 2 diabetes, but it still affects a lot of women. So is this truly a metabolic condition? Is it something that you've looked at? And is the pathophysiology, the insulin resistance that is kind of a part of PCOS, is that similar to type 2 diabetes? Okay, so this is kind of a tough one to answer, and I should answer it in the context that the name of PCOS recently changed. It's now, I think it's polyendocrine metabolic syndrome. That's what we're now calling it, which is a good thing because it captures this kind of metabolic aspect. It's really difficult to study, first of all, like looking at what's happening to ovaries, which are internal and you can't study them easily, is really difficult.

52:20What we think happens, one of the things that may be happening in some people, is that excess insulin is driving androgen production and that that is causing some of the symptoms of PCOS with the new name. So there has been interest in whether we could use specific dietary approaches to help manage it. And there is evidence we absolutely can. So weight loss, like I said, weight loss is going to reduce insulin, guaranteed. And where we have weight loss trials, you definitely see improvements in all of the symptoms of PCOS. What then becomes challenging and a kind of interesting question is what about those women who have PCOS, and I shouldn't say polycystic ovaries because not all do, but they have this poly endocrine metabolic syndrome.

53:09What about the women who don't seem to have insulin resistance because there's some of them? I don't think we know the answer to that yet. Like when I see patients with this, I definitely recommend a dietary approach, including weight loss if it's appropriate, that does focus on lowering insulin exposure. So reducing carbohydrate, increasing protein to a certain extent, increasing fiber and all of that goodness. So you can hear the same principles coming up, but this is one area where I think we definitely need to be doing a lot better with diet. We should be doing better studies measuring insulin 24-7 if we can and looking at the impact on the symptoms of this condition.

53:54In that context, is increasing protein going to reduce insulin? Oh, I love this question because everyone thinks, which is true, protein produces a big insulin spike. It does, but it comes down really quickly. When we think about the detrimental impacts of insulin, it is primarily basal insulin. It's fasting insulin because what that means is your body is exposed to elevated insulin 24-7. So it's elevated during the night when you're sleeping, it starts at an elevated concentration. Then you eat, it goes even higher, stays high, doesn't really come down. So when we think about hyperinsulinemia as being detrimental, the best way of capturing it is probably fasting insulin.

54:41That's telling you people are exposed to fasting insulin all the time. And what we see with that high protein, low carb type of diet, the data clearly shows that 24 hour insulin exposure reduces massively because you're just getting that nice peak after a meal. That's normalizing glucose and insulin comes straight back down. Do you see any merit for anyone to measure fasting insulin? Because as I'm sitting here and hearing you talk about the effects of elevated insulin, I have to imagine that if you're just measuring blood glucose, your blood glucose biomarkers might come back as normal despite having high insulin because the pancreas is, I guess, just doing a good job to compensate at that point in time.

55:29Is measuring fasting insulin, is it reliable? Is it helpful? So it's definitely true that glucose isn't giving you the whole story. So for example, probably about 60, maybe 70 % of the population have elevated fasting insulin, depending on how we define it, how it's measured. And maybe 12, 13 % have type 2 diabetes, depending on the population. The question is, is fasting insulin, though, giving you data you could get from other ways? For the vast majority of people, the people who have elevated fasting insulin are going to have an elevated waist circumference, or some of those are the classical markers of metabolic dysfunction will be elevated, you know, maybe triglycerides.

56:08There are some people that probably, for whatever reason, maybe it's genetic, have elevated fasting insulin. One of the challenges is that it's not easy to measure. From memory, from having done this in a lab, you've got to freeze the sample quickly. So you can't do it, like for example, in a GP practice, they don't do it because it's not practical. And then you've got to get an assay that is then standardized pre and post. So sometimes there is marked inter-assay variability. That means you run the same insulin sample on one assay and then another, and it gives you a completely different result.

56:46So what you want to be sure of is that there is standardization so that you're not comparing your before diet result to an after diet result that's not been validated, if that makes sense. So pragmatically and practically, it's very difficult to get a good insulin measure that you can rely on. You mentioned sleep before. How impactful is sleep regularity or duration when it comes to our blood glucose control? It definitely has an impact. We did a study in type 2 diabetes on shift workers who were working in the NHS. As part of that, you review the data on night shift workers and people who do day shift work with and without diabetes, and you see elevated glucose independent of other factors as a result of shift work.

57:36So it is meaningful. And it's not just glucose. I think there's pretty clear data that the disruption in rhythm is what's detrimental. I think, I don't work in this area, and I've got to admit, circadian biology I find really complicated. But seeing talks from people who work in this area, what is the most detrimental is going from night to day shift and then back again. If people only did night shifts, they would probably adjust and I think they would be fine. What's difficult is that you just throw your body clock and your cell clocks out of whack. So that's the really challenging thing. And the question is, so my clinical interest and our research interest is, can we prescribe diets or like exercise snacks or whatever it might be that you can mitigate the detrimental impact of night shift work?

58:27I don't know whether we can. What's your hypothesis for someone listening now I was thinking, well, just give me the best we've got. I say this, and if someone's working in the NHS or they're a taxi driver and it's a really tough job, they're going to laugh at this. But I do wonder where something like exercise, snacks or HIIT could be useful. It's not asking a lot of time. If you've done a night shift, the last thing you want to do is go to a spinning class for 45 minutes. I do wonder whether short, intensive bouts of physical activity might help reset metabolism and improve the detrimental impacts from the night shift.

59:05But I don't know. But that seems to me, because you don't want to recommend something that's crazy, but seem to me like it might be practical, but also effective. So on that, practically, and I know this hasn't been studied yet, but when you say exercise snacks, I'm thinking in my head, someone who's overnight, every hour or couple hours is doing some air squats or some star jumps. Is that the kind anything we're talking about. So our data shows, unsurprisingly, because it's in a hospital, people are walking a lot during a night shift. So there is another thing on a night shift in a hospital, and this is probably true for most shift workers, that food availability is crap.

59:43So there's vending machines. They're lucky if they have a microwave. So already you've got a barrier that the only thing you can have is unhealthy foods. But even apart from that, it's the following day. So what often people are having to do is either like stay awake for a little bit. So their working day is longer than 24 hours. Like the longest day they have is following a night shift. And naturally, that's when everything falls apart. That's when they're more likely to have something unhealthy. And that's where I'm wondering in the day after the night shift, that a high intensity activity like five bouts of 20 seconds or three bouts of 20 seconds of hit might be useful.

1:00:25Even if I'm saying that, that sounds mad to me, like knowing the kind of people, how hard they have to work overnight. But if it helps, it helps. Okay. So we'll stay tuned on that story. Before we close this out, and clearly I'm going to have to get you back on because there's so much more for us to explore together. I do want to come back to GLP-1s. We mentioned them before. Specifically with regards to the effect that GLP-1s may or may not have on muscle? And then what is the downstream consequence of that for blood glucose control, metabolic health? And I caught some commentary from the recent ADA meeting and Samuel Klein got up.

1:01:08I'm not sure if you saw this, but he kind of got up and made the case that the whole GLP-1s destroy muscle narrative has been somewhat misread. What's your take on that? That would be my take too. I almost think the alarm about this I only see on Instagram or social media. I don't see at any of these meetings people concerned about the loss of lean muscle mass. What's really tough is that we haven't had much data on it, but we are now getting data. And I think what it shows is, yes, people lose an absolute amount of lean muscle mass, but there's now data showing that the proportion of your weight that comes from lean muscle increases.

1:01:46So because your fat mass is coming down as well. So it's about proportionality. Now, of course, as Stuart Phillips always reminds us, lean mass isn't necessarily just muscle. But again, what the data is showing is that relative strength and relative strength seems to increase. So if you imagine someone who's lost 30 kilograms, they can now move much more easily. but because they've proportionally maintained lean muscle mass we hope it's muscle mass they're actually stronger they're actually more functional so i don't see outside of instagram that people are concerned by this and it's kind of weird to me that people would think that there is something special about glp1s yes weight loss is always going to encourage people to lose fat and lean muscle mass, but there's not a GLP-1 receptor on bone cells or muscle cells.

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1:03:50I think that point that you made there about lean mass, not all lean mass being muscle is really important because you can sometimes look at the raw data of lean mass loss and from that be a little bit more worried than perhaps we need to be. But when you break it down and look at what is that lean mass, is it water, is it glycogen, is it connective tissue, is it fat that's stored inside muscle, and you factor that in, then it's very likely that there's less muscle being lost anyway than what's reported as the absolute amount. Right. But I also think it's almost like we've forgotten what matters.

1:04:25so it's like you ask the question you know what's the consequence of potentially losing muscle for metabolic health well we know the answer to using glp1s on metabolic health they overwhelmingly improve metabolic health like they prevent heart attacks they get rid of diabetes normalize glucose lower liver fat so that's what matters right to patients to us what's the effect on metabolism but also when it comes to why do we care about muscle strength and functionality Again, what that data is showing is people are just as strong and they are just as functional and largely more functional after using a GLP-1.

1:05:04Or having a fracture, which that missing piece of data you're referring to, which is actually looking at strength, is providing some comfort that the metabolic health benefits are not coming at the cost of frailty and functional independence. There's some secondary data which compared GLP-1 use to DPP-4 inhibitors. And it was kind of a modelling study. And what that suggests is that fragility is less with GLP-1s than DPP-4 inhibitors that also improve glucose. Again, I guess to me, it's like the lack of data suggesting that we should be concerned against that we should definitely be concerned online.

1:05:45Like I said, if someone is 130 kilograms, the impact of that excess adipose tissue on every aspect of their health is the thing that's going to be hugely detrimental. Once you remove excess adipose tissue, particularly internally, everything improves. But then you mention bone. But again, I would come back to, well, if there aren't GLP-1 receptors on bone, it's a question of weight loss. And it's a question of if sustained marked weight loss over many, many years would impact on bone. Don't get me wrong. I'm not saying that we need to forget nutrition and forget exercise. I think they are important.

1:06:28But I would emphasize, I think a lot of the, oh my God, we should put warning signs on these, is completely in conflict with the data that's out there. If we zoom back out and think about this through a kind of macro lens, and you've established that a lot of type 2 diabetes is driven by excessive energy intake and kind of lipotoxicity. But then if you ask the question of, well, what's driving that excessive energy intake, you come to things like food environment, socioeconomic disparity, all these other factors that exist. On the food environment, do you think the emergence of GLP-1s will shape the food environment, changing the foods that are showing up on shelves, which will then have a positive effect on metabolic health?

1:07:18I think that is 100 % more likely than us ever succeeding in changing the food environment by policy means. We should absolutely do it. But I think the thing that stands a better chance. In terms of the ubiquity of improving healthy foods, yes, I think in the next 5, 10, 15, 30 years, as GLP-1s have greater penetrance in the population. So right now, we've got a massive supply issue that we can only keep people on them for a certain amount of time because we don't have enough to go around. That will disappear. We will be able to keep people on them long-term. We will, fingers crossed, as the time goes on, be able to give a GLP-1 or co-agonist to people who need them.

1:08:06Yes, I think it will change the food environment. I'm going to get you to come back and talk to me about continuous glucose monitors and other things. So I'm not even going to open that can of worms just here. To close this out, firstly, was there anything that we didn't get to today or that you wanted to expand on that we've covered? One other thing I thought might be worth adding with the GLP-1 stuff. So someone in our group published a paper showing weight regain on cessation of GLP-1s is greater than from behavioural interventions. And I thought that was quite interesting to mention because it's something that comes up.

1:08:40It's like, oh, well, everyone just regains weight. And it's true. I don't know whether you think this is interesting, but I think it comes down to the fact that once we fix the supply issue, people can stay on them. They'll stay on a low dose. But also, the impact that a behavioural intervention might have on top of a GLP-1 to make sure that people are eating healthier and staying off them long-term. Coming down the pipeline, you alluded to your research on shift workers. Is there anything else coming down the pipeline in metabolic health research, type 2 diabetes research that's new or emerging, whether it's diagnostics or interventions that is exciting you and we should keep an eye out for?

1:09:20I think digital health is really exciting. I think what we're able to do now with just supporting patients on dietary interventions, like GLP-1 data, I really hope the outcomes improve if you just have a very light touch digital intervention teaching you, put a bit more protein on your plate, make sure you're adding some veggies and fibre. I think digital health is going to continue to change the way we can deliver dietary and behavioural interventions. Beautiful. Well, thank you very much, Nicola. We're all super grateful. I really love this conversation and you have an open invite to come back and join us anytime.

1:09:59I can't believe we talked for like an hour and didn't touch on CGMs. No, that was purposeful. We'll carve out an entire episode for that, I think. Great. Thank you very much. Not at all. Thank you. There you have it, friends. I hope you enjoyed this episode. If you did and want to stay up to date with future episodes, be sure to hit that subscribe button on YouTube and follow on Apple or Spotify. Finally, thank you for showing up and the effort that you're making to take control of your health. I look forward to hanging out with you again in the next episode.