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Amino acids and the changing face of the 𝛼-cell in diabetes
Until relatively recently, diabetes was a terminal condition. Today, over 1 in 10 people are living with it, which says something about the success of insulin as a treatment, and also the concerning state of global nutrition. So, we've probably got diabetes pretty well figured out. Right?
Dr Alexander Hamilton speaks with us about his research into alpha cells, amino acids, and why we might need to rewrite the text book on diabetes.
Read the original research: https://doi.org/10.1016/j.peptides.2023.171039
00:00:04 Will Mountford
Hello I'm Will, welcome to researchpod.
00:00:07 Will Mountford
Once Upon a time, not too very long ago, diabetes was a terminal condition. Those with type one diabetes, often not surviving more than a few months after birth. Today, over one in 10 people are living with it, a number that's continuing to rise. It is a testament to the success of insulin as a treatment and also the concerning state of global nutrition.
00:00:29 Will Mountford
But with such a huge prevalence of the condition and the successes in its management, you'd think we know just about all there is to know about diabetes.
00:00:37 Will Mountford
Right. Today I'm speaking with Doctor Alexander Hamilton about his research into alpha cells, amino acids and why we might need to rewrite the textbook on diabetes.
00:00:50 Will Mountford
And joining me from Lund University's Faculty of Medicine is Doctor Alexander Hamilton. Hello there.
00:00:55 Dr Alexander Hamilton
Hello.
00:00:56 Will Mountford
For myself and for everybody, listening at home, could you tell us a bit about yourself, your work and what's led to where you are?
00:01:03 Dr Alexander Hamilton
Metabolism was always something I was really interested in, and then it just kind of grew from there. Like I initially became a lab technician straight out of university and that was at a diabetes center. And then as a kind of why I specifically have gone towards the alpha cells and the eye that I suppose is because I think it's an area which we don't understand a lot about. There's a lot of research on the beta cells, which are the cells that.
00:01:23 Dr Alexander Hamilton
Secrete insulin and of course, everyone knows insulin is very important in diabetes.
00:01:27 Dr Alexander Hamilton
I am a researcher at the moment I'm a postdoc, kind of employed by London University, but my grant is an international grant, so I do a lot of my work across the Oresund Strait in Copenhagen, so I kind of work between the University of Copenhagen and London University. My Swedish group is run by leaner liaison, predominantly kind of works.
00:01:48 Dr Alexander Hamilton
On B cells, which she also does a bit of work on alpha cells, she looks at kind of micro RNAs also looks at how these cells function, how they secrete the hormones so to say how beat cells secrets insulin or how and how cell secretes gluco?
00:02:02 Dr Alexander Hamilton
My Pi in Denmark is called Yakov Canuteson. Someone who actually did their postdoc where I did my pH. D When I was at the University of Oxford. His work basically centers on the alpha cells, so his focus is completely on the alpha cell and he's trying to work out how glucose secretion is regulated. But looking at it away from just looking at it and how it's controlled by glucose but looking at more.
00:02:22 Dr Alexander Hamilton
How it's controlled by fatty acids and also what I look at, which is amino acids.
00:02:27 Dr Alexander Hamilton
There's a lot of fundamental knowledge we don't actually understand, so I think my approach to science is to work on things which have an impact, whether that be, you know, producing new therapeutics or actually answering fundamental questions that will actually lead to differences in the textbook, not just the paper. So I think that's why I'm.
00:02:43 Dr Alexander Hamilton
Kind of in this field.
00:02:48 Will Mountford
What would you say the state of the world is in regards to diabetic health currently in 2024?
00:02:54 Dr Alexander Hamilton
Well, I think it's pretty one of the largest kind of health problems. We have cardiovascular disease, cancer, but you also have diabetes.
00:03:02 Dr Alexander Hamilton
Is around over 500 million people living with it right now and that's forecast to increase to around 783,000,000 by 2045. So this is a lot. This is almost one in 10 population and that might also be people with condition called pre diabetes that occurs before this and some people are undiagnosed and it's a serious problem and I think a lot of people view diabetes as.
00:03:22 Dr Alexander Hamilton
Ohh, it's just high blood sugar, but that high blood sugar also causes secondary complications.
00:03:27 Dr Alexander Hamilton
Increases your risk of cardiovascular complications like stroke, heart attack, atherosclerosis. These kind of things. It causes amputation because you get neuropathy, so you get loose sensation in your peripheral feet and things. So it's one of the leading causes of amputation. It might be the leading causes retinopathy, which is where you get microvascular complications in your eyes.
00:03:48 Dr Alexander Hamilton
Heights of blindness. So it's a real problem. And although we have insulin to treat it.
00:03:52 Dr Alexander Hamilton
And also other drugs like metformin, GLP 1 receptor and agonists, and various other things. There's still a problem. We still have people developing these complications and there's still more that can be.
00:04:03 Will Mountford
Something that I think has been widely regarded as a.
00:04:06 Will Mountford
Kind of a fixed thing that we've invented insulin and we have solved the monolithic form that is the one type of diabetes that there is. So is that a a challenge in terms of addressing public health awareness as well as public health concerns?
00:04:21 Dr Alexander Hamilton
Yeah. And I think just for the listeners, people with type one diabetes, which is where you have autoimmune destruction of your beta cells and this is often people have this from a young age, they were just go straight onto insulin, whereas type 2 diabetics, which is usually where people have insulin resistance and then they beat cells.
00:04:36 Dr Alexander Hamilton
They they would initially go on to drugs like metformin or drugs like sulfonylureas and various other things, and then eventually they might be on insulin. And it seems very good. But the problem with it is when you take it and you inject it, you can be at risk of hypoglycemia. So that's where your blood glucose drops to very low levels. And that is very dangerous, like it's like coma.
00:04:57 Dr Alexander Hamilton
I mean, even in the worst case scenarios, that and with the current instant treatment, it's very difficult for a diabetic to keep their glucose levels as good. Well, as someone who's non diabetic and the fluctuation in glucose levels causes those kind of secondary complications later in life and also just the daily injections as well, that can be difficult.
00:05:14 Dr Alexander Hamilton
There has been advancements where you've got insulin pumps and things like that, which make it easier, but these aren't widely available to people with diabetes, so there are still problems and people with diabetes still have a lower life expectancy than someone without one could be the answer to some of those problems which we get into later.
00:05:31 Will Mountford
Itself by explaining what's happening on an institutional level at the Lund Diabetes Centre. Then we'll get to the personal level and this paper specific work we're talking about today.
00:05:41 Dr Alexander Hamilton
The center is, I'd say it's very eyelet focused compared to other diabetes centers around the world. There's a big focus on beta cells on our work on beta cell lines.
00:05:51 Dr Alexander Hamilton
And groups basically looking at various different aspects of that. So you have groups looking at the epigenetics of that. So looking at how epigenetic changes in people with diabetes and without effect contribute to diabetes pathogenesis, but you also have groups looking more at the function. So how does the beta cell?
00:06:11 Dr Alexander Hamilton
Of the cells as well, how do they actually secrete? How does exocytosis occur and the like? The actual function basis of that? There's also work looking at stem cells so.
00:06:20 Dr Alexander Hamilton
They get stem cells and then try and convert them into beta cells and then they can use this as a model to look at how when they say knockout a gene that comes up as being involved in diabetes, how when they knock that out, how that can affect instance secretion. So there's a lot of work on that. There's also the Teddy study, which is one of the major type one diabetic studies in the world. So that's more of a.
00:06:40 Dr Alexander Hamilton
In the work where they get patients and they analyze various aspects of people type, generally children with type one diabetes.
00:06:47 Will Mountford
You mentioned earlier, Glucagon in diabetes and we've talked about type one and type 2 diabetes. But to establish the the model as things stand, what is Glucagon? What does it do in a normal regulated digestive system and how does that change in a diabetic condition?
00:07:05 Dr Alexander Hamilton
So Glucon is kind of the main.
00:07:07 Dr Alexander Hamilton
And responsible for increasing your blood glucose levels. So the way glucose is controlled in your body is when you eat a meal, say, and you have carbohydrates that will increase your blood glucose levels and then insulin will bring those down.
00:07:20 Dr Alexander Hamilton
But to prevent yourself becoming hypoglycemic, which is kind of low blood glucose which is quite dangerous, you also have glucon there which can increase glucose levels and it does this predominantly by being secreted from the pancreas as insulin as as well and then acting on the liver and basically telling the liver to produce glucose. So the liver can produce.
00:07:40 Dr Alexander Hamilton
Glucose, either via breaking down glycogen, which is like a storage form of glucose.
00:07:45 Dr Alexander Hamilton
And breaking that down into individual glucose molecules, individual sugar molecules, or by actually synthesizing glucose from other substrates, these can be amino acids, lactate, glycerol, so glucose's main role is basically to prevent hypoglycemia and to basically keep your glucose levels at a normal level. And it does that.
00:08:05 Dr Alexander Hamilton
In counteraction within silent, so it's the two of them that control that.
00:08:09 Dr Alexander Hamilton
In diabetes that goes wrong. So insulin first of all, as most people will know, stops working in diabetes. So in type one, you don't get your beta cells are destroyed by your immune system.
00:08:19 Dr Alexander Hamilton
This is the type of diabetes you get often when you're younger, and that means that basically, when you eat a meal and you get high glucose levels, you can't bring those down again. So they have to inject insulin. You then have type 2 diabetics who have. It's often caused by lifestyle, whether that be age or obesity as well as genetic predisposition as well. And that's caused by kind of insulin resistance.
00:08:40 Dr Alexander Hamilton
Peripheral insulin resistance. So your basically tissues like your muscle and your fat become resistant to it.
00:08:45 Dr Alexander Hamilton
Ellen and this means they can't because insulin basically tells them to take up glucose. They can't do that anymore. So your blood glucose levels increases, and this puts stress on the cells that produce insulin because they're basically not working. And that can also cause their dysfunction. And that's kind of what Type 2 is. And that's generally how it's looked at. So you just look at an insulin, but at the same time, you've also got dysregulation.
00:09:06 Dr Alexander Hamilton
Of Glucagon, so Glucagon is usually in a normal state when you're at low glucose, glucose will be high and when you're high glucose, glucose will be low.
00:09:15 Dr Alexander Hamilton
But you kind of get an inversion of that. So you say when you, a diabetic, eats a meal rather than their Glucagon being suppressed, it can actually be upregulated. And that means you get basically increasing blood glucose levels. And that together with the the low levels of insulin means you're kind of in a state where you're promoting high blood glucose levels. It's kind of.
00:09:36 Dr Alexander Hamilton
Low insulin and the high glucon kind of causing a perfect storm where you've got very high glucose levels in your.
00:09:41 Dr Alexander Hamilton
But and then also there's another problem with people who take insulin. So this can be this will be people with type one diabetes can cause you to go hypoglycemic when you inject it because you can kind of overdose basically. And then what happens in diabetics is they usually say in non diabetics when our blood glucose levels come down, you have Glucagon which counteracts that and that keeps you at like a normal glucose.
00:10:04 Dr Alexander Hamilton
But in people who inject insulin, it can go down because they're kind of overdosing, and then there's no real Glucagon response. They lose the glucon response, the mechanism why that happens is not completely understood. There's not really consensus, but they lose this response, and that can put them at real risk of becoming hypoglycemic and hypoglycemia, which is low glucose levels, is very risky.
00:10:23 Will Mountford
And you mentioned at the start of run said that the metabolites involved in digestion include amino acids amongst others include.
00:10:30 Will Mountford
Lactates for Glucagon over secretion. What does that over secretion do in terms of amino acids in digestion, circulation? Where do they go up?
00:10:40 Dr Alexander Hamilton
Down it's a bit confusing so. So if you had a glucagonoma where you have basically a tumor in your alpha cells, which means you hyperscript Glucagon cause Glucagon. Basically it doesn't just control glucose levels.
00:10:51 Dr Alexander Hamilton
A lot of this new research is about it controlling amino acid levels as well, and it basically tells the liver to take up amino acids and these amino acids either are degraded via urea, agenesis and urea is excreted by urine. That's where I.
00:11:05 Dr Alexander Hamilton
Called urine or it can also be used to convert to glucose and glucose basically is one of the major controllers of this process, so it controls your plasma amino acids. So if you've got too much Glucagon, you'll lower your amino acids. And if you have too little, you will increase them.
00:11:21 Dr Alexander Hamilton
Now, in the setting of diabetes, a lot of the new research suggests what happens is the lot of people with diabetes, they'll have fat in their liver. When those ectopic fat, so they'll have what's also known as non alcoholic fatty liver disease. And this means they've basically got fat in their liver and that causes a variety of problems. It can cause insulin resistance so their liver becomes.
00:11:41 Dr Alexander Hamilton
Resistant to.
00:11:42 Dr Alexander Hamilton
Insulin and this is insulin resistance. As you know, one of the main facets of type 2 diabetes. But a lot of this research also suggests that fat can cause Glucagon resistance. So that means that they kind of secrete Glucagon, but then because the liver has become resistant to Glucagon, you actually get an increase in amino acids.
00:12:02 Dr Alexander Hamilton
Because the liver has become unresponsive to gluons, so that means it's not reacting to gluon, and that means the amino acids levels increase in type 2 diabetes. And that means these amino acids then act to stimulate glucose formation because amino acids they increase glucose.
00:12:17 Dr Alexander Hamilton
Basically, and that means you get this hyper secretion of Glucagon which basically results in the liver producing more glucose because you have glucose resistance in terms of the amino acid pathway. But this doesn't seem to affect the action of glucon on glucose. So you get this. This is kind of one of the main drivers. So that's basically what a lot of the research by fellow researchers at the University of Copenhagen.
00:12:38 Dr Alexander Hamilton
Suggested I would say like this is by number means a settled issue like it's a theory. This liberal facial is known as the liberal axis, but it's kind of a they're proposing. This is how Glucagon becomes dysregulated in diabetes so that you get this glucose resistance, an increase in amino acids, and then that causes the hypersecretion of glucon.
00:12:58 Dr Alexander Hamilton
But in a standard setting, what I'd say is Glucon would lower I mean acids, and then if you've got less glucon, you should get higher amino acids. But in Type 2 diabetes it's a bit.
00:13:07 Dr Alexander Hamilton
Different.
00:13:08 Will Mountford
That.
00:13:08 Will Mountford
Loop of Glucagon secretion amino acids cocon amino acids back is that operating on the scale of hours days?
00:13:19 Dr Alexander Hamilton
That's a good question. I'm not completely sure, but I'd say it's more like an acute thing. So say surplus like your amino acids, the change in their concentrations would generally be dietary. So say if you eat a protein rich meal that would increase your, I mean acid levels, but also somewhat affected by whether you're fasted or in a fasted state. But I'd say that it's more to do with.
00:13:39 Dr Alexander Hamilton
Dietary uptake and then I'd say it's acute, so it's probably very quick. So you eat amino acids and then that will trigger glucose secretion. Glucon then acts on the liver and will cause sealing in the liver, which results in the uptake of amino acids and then their breakdown basically.
00:13:59 Will Mountford
To address the action of Glucagon as a hormone, what does that binding site look like? If we can get into maybe even the atomics of it, what happens at the moment of contact in that binding?
00:14:10 Dr Alexander Hamilton
So Glucon is a hormone that basically means it's a chemical messenger. It gets taken into the bloodstream and then has effects on.
00:14:16 Dr Alexander Hamilton
And peripheral sites.
00:14:18 Dr Alexander Hamilton
Now the liver cells, their petites will have Glucagon receptors and glucon will bind to these receptors and the Glucagon receptor is a type of receptor known as a G protein coupled receptor. There's lots of different G protein coupled receptors, so glucose receptor is one. All the Adreno receptors are all different protein coupled receptors. So these are the receptors adrenaline works on.
00:14:37 Dr Alexander Hamilton
And various other hormones will work on different G protein coupled receptors and in basic terms these G protein coupled receptors are basically it's a receptor like is coupled to another protein known as G protein and I won't go into too much detail about how it works, but it basically activates that G.
00:14:52 Dr Alexander Hamilton
Protein then that G protein will act and cause an increase in something known as a secondary messenger. So in the case of Glucagon, this causes an increase in a signaling molecule known as cyclic GMP by basically activating an enzyme known as adenylate cyclase and that enzyme converts ATP, which is kind of the energy currency of cell it's.
00:15:14 Dr Alexander Hamilton
Molecule into SCMP. It's the important thing here is basically that the glue combines. Then you get this triggering and you get this big increase in psychopomp in the cell.
00:15:22 Dr Alexander Hamilton
That site click amp can then act on kinase. Kinases are basically proteins which phosphorylate other proteins. Phosphorylation is kind of a it's like an on and off switch for various different things and the big increase in.
00:15:36 Dr Alexander Hamilton
Psyche.
00:15:37 Dr Alexander Hamilton
MP causes activation of PKA which is protein kinase A.
00:15:42 Dr Alexander Hamilton
And then PKA has a variety of targets so it can affect you know, calcium channels in the membrane. It can affect different enzymes, it can affect various things. It's got quite a wide repertoire of things that it can affect and it depends on the cell types in, in the participates when you get activation of protein kinase A that will phosphorylate an enzyme.
00:16:02 Dr Alexander Hamilton
You mentioned lock and key in result to enzymes, so that will phosphorylate glycogen synthase and that will activate glycogen synthase and what glycogen synthase does in simple terms, is it. Basically it's one of the main enzymes responsible for the conversion of glucose into glycogen. So glucose is like a single sugar molecule and that will glycogen synthase does, as it basically makes into a big chain a big glycogen chain, and that's how it's.
00:16:25 Dr Alexander Hamilton
The water. Sorry. Glucose. The phosphorylation will actually inactivate like the synthase. I've got the wrong way around, so it will inhibit that enzyme. And that means you'll reverse the reaction. So you'll get a conversion of glycogen back into glucose.
00:16:41 Will Mountford
When it comes to intake of energy and expenditure and metabolism, imagine having breakfast that is food going in and then before you have lunch, there will be this line on the graph goes up. This line goes down and take me through it in a a fundamental.
00:16:55 Dr Alexander Hamilton
Level, yes. So basically when you have a meal like your glucose levels will increase and that will.
00:17:01 Dr Alexander Hamilton
Stimulate insulin, which then tries to reduce them at the same time that will inhibit gluten.
00:17:07 Dr Alexander Hamilton
On so generally when you're in that postprandial state, so after meal insulin is stimulated and Glucagon is inhibited and then after that's passed, once you're in the fastest state because your insulin has acted, the glucose levels begin to fall because they're taken up by the liver to produce glycogen or also taken up by fat tissue to produce fat. Then as the glucose.
00:17:27 Dr Alexander Hamilton
Those drops, that's when glucon then begins to act, and basically it signals to the liver and tells it to produce glucose. Basically, it keeps that kind of glucose homeostasis, so keeps glucose at a level.
00:17:38 Will Mountford
To pick the metabolization of amino acids versus glycerol, lactate and other metabolites apart. What sets amino acids apart from any of those or them from each other.
00:17:51 Dr Alexander Hamilton
I think with those three you've chosen are kind of the substrates for gluconeogenesis. So they're the things that can basically generate. You can basically use to convert into glucose in the liver, I'd say more where they're from, I guess, like glycerol is generally from.
00:18:07 Dr Alexander Hamilton
So, glycerol, when we talk about fats like the fats you.
00:18:11 Dr Alexander Hamilton
They're in the form of triacylglycerols or tags and they what A tag is getting very into chemistry now, but it's basically a glycerol molecule which is like the backbone, and then you've got three fatty acids attached. That's what it's triacylglycerol these three fatty acids, glycerol. And then when this gets.
00:18:30 Dr Alexander Hamilton
In the body you've got process known as lipolysis which is where the in your adipose tissue. The fat is basically stored as triacylglycerides, so these these tags basically and then when it gets broken down it gets broken down into fatty acids which can be used by different cells to produce energy. And then this glycerol backbone that can then be used and converted into.
00:18:48 Dr Alexander Hamilton
Goes, so it's kind of more the origin, whereas amino acids would more come from they're from protein rather than fat. They can also your muscle also has stores of amino acids so it can release amino acids and things like that and then lactate is when you hear people talk, lactic acid lactate is they're actually talk about lactate. So lactate is it's basically a byproduct.
00:19:09 Dr Alexander Hamilton
Of when your body is trying to produce energy, but it can't when it's trying to produce energy via anaerobic respiration, which is respiration without oxygen.
00:19:18 Dr Alexander Hamilton
So your body can either produce it via aerobic respiration, which is in the mitochondria, where you use oxygen, or anaerobically, and that's what lactate is, and this lactate can also be used and converted into glucose, and there's kind of a cycling between lactate and glucose, but I'd say amino acids, it's more like their origins from proteins. They can also be those.
00:19:39 Dr Alexander Hamilton
Other two are kind of more byproducts, let's say of other reactions. Whereas amino acids can actually also be used to produce energy, so they don't just produce glucose like the fatty acids and the glucose that's talked about. I mean, acids can also be taken up into the mitochondria and used to produce energy or ATP, which is kind of the energy current.
00:19:56 Dr Alexander Hamilton
So that's kind of how they differ and also amino acids. There's like 20 of them. So it's not like when you talk about glycerin, lactate or like one molecule amino acids are 20 and they will.
00:20:04 Dr Alexander Hamilton
Have differential effects.
00:20:06 Will Mountford
Amongst that broad group, which particular amino acids, if any, have the most to bear on your research?
00:20:12 Dr Alexander Hamilton
For my research, if we look at like the literature, alanine is one that always comes up. Cystine also comes up. They these have big effects on drug consecration.
00:20:22 Dr Alexander Hamilton
Glycine and glutamate have also been shown to stimulate glucose.
00:20:26 Dr Alexander Hamilton
So yeah, and it's just working out the mechanisms by which how they do this. So we.
00:20:30 Dr Alexander Hamilton
Know.
00:20:30 Dr Alexander Hamilton
These stimulate glucose fusion, but we don't necessarily know how.
00:20:34 Dr Alexander Hamilton
Arginine, as well this is often researched. Then you've also got some people who talk about tyrosine stuff, but the mechanisms by those which those work are quite poorly understood and even the ones we know like there's some ideas of how they work, but they're not substantiated and there's definitely not consensus and that's kind of the main thing with the alpha sell field that no one, there's no consensus.
00:20:54 Dr Alexander Hamilton
I see.
00:20:56 Will Mountford
Honing things down even further to the individual cell level, here the alpha cell involvement that you've been researching that's defined the paper that we're working on. Yeah. Can you tell me more about the amino acids and their involvement here, the effects of timing and how?
00:21:16 Will Mountford
What your research is doing is putting forward something of a different view to the accepted textbook model.
00:21:23 Dr Alexander Hamilton
Yeah. I think generally before like when to say with the beta cell, just the cell that just insulin, we kind of know how it works and it's regulated by glucose, glucose increases and you get an increase in instance creation and researchers looking at that and including a PhD supervisor, actually they then shifted to look at alpha cells.
00:21:43 Dr Alexander Hamilton
But they tend to find it looking at it in terms of glucose as well, and a lot of the current models we have rely on the alpha cells sensing glucose and then that leading to glue concentration. So the idea is that low glucose when the glucose is low.
00:21:59 Dr Alexander Hamilton
The alpha cell senses this and you get glucose secretion.
00:22:03 Dr Alexander Hamilton
There's some problems with that in that means the cell is most active when the fuel source is low, so the when energy is low, the alpha cell is most active. If it's using glucose as its primary fuel.
00:22:15 Dr Alexander Hamilton
It kind of doesn't add up because it's most active when the fuel it uses is at its lowest, so there's kind of been a rethinking around that and it's genuine, pushed by my Pi I work for in Denmark so Jacob could Hudson, who's looks more at OK, what's high during in the faster to say what fuel is available? And he's actually done a lot of work on fatty acids.
00:22:37 Dr Alexander Hamilton
Because these actually increase when you're fasted, so you get an increase in fatty acids and he's shown that these are important in terms of glucose secretion and then at the same time, there's been this emergence of the role of amino acids and that's caused by the fact that when we look at Glucagon and we disrupt its action, we see amino acids go up basically.
00:22:57 Dr Alexander Hamilton
Which and we also know Amelia has to stimulate glucose.
00:23:00 Dr Alexander Hamilton
But in terms of the paper I wrote, I think what I'm more trying to say is that OK, fatty acids are important, but our amino acid is actually important. When you're fasted. And I think generally, I'd say that there may not be because they don't increase in the same way by acids. You generally see amino acids actually drop when you fasted because they start to be utilized by the liver to produce glucose. The actual plasma levels don't increase.
00:23:22 Dr Alexander Hamilton
There's some that increase, so the branch chain amino acids, but these are actually not. They're the few amino acids that don't stimulate glucose.
00:23:29 Dr Alexander Hamilton
So yeah, that's I think it's more likely that the effect of amino acids on Glucagon is via kind of perhaps dietary. So when you eat, say, a high protein meal that will stimulate glucose secretion and it may actually be separate the control. The fact Glucon is active in the fastest state or when glucose levels are low.
00:23:49 Dr Alexander Hamilton
More result of the metabolism of fatty acids and the interrelationship between fatty acids and glucose. What the paper does is it kind of talks about what glucose does, and then it's about this has led to basically people looking at it just in terms of glucose and then what the paper is really about is that the it's about the shift.
00:24:09 Dr Alexander Hamilton
In the research that I'm doing, like the research used to just be ohh, glucon regulates glucose, but now it's more shifting towards OK, but it has the IT also controls amino acids. It controls how amino acids are it controls amino acid homeostasis as well, and there's like emerging research and how it's regulated and things like that. So I think going along those lines might be a better way.
00:24:34 Will Mountford
What does this new view on alpha cell involvement and activity mean? For I know the past 30 years of textbooks talking about diabetes are people going to have to go book and amend a lot of figures and diagrams to say, you know, ask the risks? See here.
00:24:52 Dr Alexander Hamilton
Yeah, I think this is generally just seen in the kind of like you just see in the academic literature. And there's, but there's still, like, you go even me, I go to a conference and it's still mostly on beta cells. So I think hopefully with this shift where we're like looking at the salon and.
00:25:05 Dr Alexander Hamilton
Anyway, hopefully we can. I think the text needs to be changed. If you look at text now, there's very little information on gluco really be like a power off or so. So I think there's it's a real. We really need to understand what what this is about. And there's really strong evidence suggesting why that gluten is really important for diabetes.
00:25:23 Will Mountford
They say that the the fatty component of diet is going to be having more, or at least more of a surprising effect.
00:25:31 Dr Alexander Hamilton
Yeah, it depends on the context. So I think after a meal when your amino plasma ministers rise, that's when you have an effect, glucose secretion, although this is still up for debate. I'm saying whereas fatty acids, they generally increase in the fastest state, but it's not necessarily dietary fatty acids because the dietary comes in the form of trial.
00:25:51 Dr Alexander Hamilton
Listerine. So that's not fatty acids per se.
00:25:54 Will Mountford
I'm just.
00:25:54 Will Mountford
Trying to.
00:25:55 Will Mountford
Like visualize this on a clock of you know fasting start to.
00:26:00 Will Mountford
Food intake to metabolism to out to.
00:26:03 Will Mountford
Then say that if fasting is when the lipids are being digested and then food amino acids in and kind of to graph things out, either on a clock or you know a line graph overtime.
00:26:18 Will Mountford
Where exactly is the?
00:26:21 Will Mountford
The new perspective of what is happening at what time to which digestive state.
00:26:28 Dr Alexander Hamilton
Yeah, it's more that. So generally when we talk about the timing, we're talking about fasting and postprandial, which means after a meal and basically what I'm saying is in the fastest state, it seems unlikely that amino acids would affect Glucagon secretion. So the fastest they would be like, say overnight when you're not eating, it's unlikely that amino acids would affect glucose secretion.
00:26:49 Dr Alexander Hamilton
Because they're not. They don't increase. Generally the ones that we think increase glucose.
00:26:54 Dr Alexander Hamilton
But after a meal where you eat protein, then that would increase your amino acids and that could be what stimulates when glucose secretion is stimulated with glucose. Stration would also be stimulated in the fastest state and that would be by fatty acids which aren't dietary taken up like whether fatty acids released from your adipose tissue. So from your fat tissue.
00:27:14 Dr Alexander Hamilton
The end to the bloodstream because when you're in a faster state, your body begins to basically breakdown fat in your adipose tissue and then release it into your bloodstream, and then it's used by the liver, and it can be used as a fuel source, but it can also be basically the use.
00:27:29 Dr Alexander Hamilton
Of fuel source when you're you're fasted.
00:27:32 Will Mountford
To think about what these findings that you're working on and the ongoing research could mean for people listening, are we in a position to say what these changes could mean for people's diet? If there's anyone who wants to take immediate action, do we have the position to tell them to do that?
00:27:49 Dr Alexander Hamilton
I'd say like with the the specific research I'm doing, it's kind of its infancy and you've gotta remember, we're looking at an isolated system. So we're saying how amino acids affect Glucagon.
00:27:58 Dr Alexander Hamilton
But I mean, I just don't. That's not their only thing. That's not that they also, I mean, I mean, I said also can stimulate instance secretion when glucose levels are high. So it's I know means simplistic that you would kind of cause if say a diabetic was lifting they might think OK if I don't eat amino acids then that would lower my glucose secretion and then therefore it may have positive effects or it may prevent diabetes.
00:28:21 Dr Alexander Hamilton
Then you also have a stimulated effect on insulin, which would be positive for diabetes, so it's by number means saying this there is in terms of diet, I think generally what most doctors would say, I'm not a medical doctor, but like what they would say is balanced diet.
00:28:34 Dr Alexander Hamilton
You know, eating healthy food, monounsaturated fats, polyunsaturated fats, a decent amount of protein displaying carbohydrate. And I'm not gonna delve into that. There is a lot of like fad diets as well, like low carbon stuff. But I don't have the expertise to talk about those. I would say there is some like, mouse research where you look at like reduce like an amino acid, like a single amino acid, say methionine which.
00:28:56 Dr Alexander Hamilton
One of the amino acids, and they see that this has quite startling effects on whole body metabolism. I think there is an interesting thing about amino acids in terms of that isn't just related to my research glucon, but they could have wider effects. And when you reduce this methionine then it has like large effects or positive effects kind of increasing energy expenditure which is good and kind of improving instant sensitivity.
00:29:17 Dr Alexander Hamilton
Which is kind of the opposite to insulin resistance or improving how insulin?
00:29:20 Dr Alexander Hamilton
Functions, but that's in mice, and that's like a lot of research in mice. And like, I think you always have to take it with a pinch of salt. Also, if, like, you were to try a diet where you just remove one, I mean, I said you'd find it impossible as a human being because, like, we're not eating a mouse's diet. We're not that these are engineered diets and labs. We're eat. We're going to the supermarket. If I'm eating like cheese or something with protein in it.
00:29:41 Dr Alexander Hamilton
It's not gonna just have like 1 amino acid. It has a multiple. So realistically speaking, there's some interesting research and diet. I I generally say like more needs to be done basically. And the nutrition field is renowned for being very like murky. So yeah, I don't wanna get into that.
00:29:58 Will Mountford
And we shouldn't be expecting the Alexander Hamilton diet.
00:30:01 Will Mountford
Advice book coming to shelves anytime soon.
00:30:03 Dr Alexander Hamilton
No, certainly not.
00:30:09 Will Mountford
Well, to focus on the science, what plans are there to put this to the test in either animal models or from collecting human data? Are there plans for more investigation along?
00:30:21 Will Mountford
This route.
00:30:22 Dr Alexander Hamilton
So yeah, there's there's lots of research on this at the moment, so there's it's a really emerging field where people are looking at their selling a different way and they're looking at it in terms of looking at amino acids, fatty acids and things like that. So we're not the only group working on this.
00:30:38 Dr Alexander Hamilton
And I think, yeah, trying to do a lot of the work we do as a mice, but also trying to work with human. I let some, we get those inland. So I think that that's something that we want to look at basically. So yeah, there's a lot of progress that can be made basically.
00:30:51 Will Mountford
For people who are listening to this maybe want to know more about your research, where can they find it? Is there anyone else who you think would have something to benefit from listening to this conversation?
00:31:01 Dr Alexander Hamilton
I think the main thing from this conversation that I'd want to suggest, I don't think it's like an action point for clinicians to act on clear. Clinicians are also aware of the role of Glucagon and it's affects. It's how it's dysregulated in diabetes and there is, I'd say, it's more for current researchers just pointing out we're kind of ignoring this area like most people research insulin. There's so much research in this, but there's.
00:31:22 Dr Alexander Hamilton
Real need to actually understand the alpha cell and how glucon is regulated, and there are some advancements with this amino acid work, which suggests there's more to it than meets the eye. And if we focus on this, we could potentially come up with like new therapies and things. And as you say, maybe like some dietary things as well, although again the stress that's that's very much in the sympathy.
00:31:43 Dr Alexander Hamilton
But like, yeah, there's a massive opportunity here to kind of understand more.
00:31:48 Will Mountford
And if people wanted to stay in touch, where could they find more from you on?
00:31:52 Dr Alexander Hamilton
There's another podcast that it I don't know if I can advertise, but I did it with. It was the Danish Diabetes Academy, or it's actually known as the Danish Diabetes and Endocrine Academy now, a podcast called Postdocs Talking, which is also available on Spotify and other things as well. And with that, I did that with the researcher Danish.
00:32:11 Dr Alexander Hamilton
Search, known as Nikolai Veva Albrechtsen and he is kind of one of the figureheads behind like this, that liver alpha cell axis I was talking about how glucon regulates amino acids and how amino acids regulate Glucagon.
00:32:25 Dr Alexander Hamilton
He's more of a clinician, so I was coming at it from the Alpha Salon, my expertise than that that he was talking more about the effects on the liver. So if you wanted more in depth and like his knowledge as well, I'd suggest checking out that podcast.
00:32:38 Dr Alexander Hamilton
I'd also suggest a lot of this glycone research. If you check out an author known as Roger Unger, who is American, he passed away recently, but he spearheaded a lot of the research into Glucagon and its importance in diabetes and a lot of this research is probably not ignored, but it's it's not got its prominence it deserves, perhaps. And I think that he kind of underlines that you need glucon to get diabetes. And it's quite striking.
00:33:00 Dr Alexander Hamilton
So I'd I'd suggest looking at that as well.