How Cells Sense and Integrate Metabolic Signals

00:00:01: The EASD presents Diabetes, Insights, Breakthroughs

00:00:05: and Innovators.

00:00:06: Hello!

00:00:07: And welcome back to EASdTV.

00:00:09: Now it's one of the great pleasures in my life To interview the winners Of various prizes that are given And lectures offered during EASds.

00:00:22: This is a relatively new award.

00:00:26: I'm delighted to introduce its winner Professor Kay Sakamoto, welcome.

00:00:30: It's the EASD Novo Nordisk Foundation Diabetes Pride for Excellence.

00:00:37: So congratulations because it is a very special award and your work has been really foundational in understanding the signalling systems that are going on that result in insulin uptake.

00:00:54: so just tell us about how you started this research and what it's led to

00:01:01: do.

00:01:02: Yeah, so that I started actually as an exercise specialist in Japan.

00:01:06: So i was fascinated by the way exercises provide a lot of different health benefits.

00:01:12: That is why we wanted to figure out the molecular mechanism And then move on to Dotsunin Diabetes Centre in Boston where people study How insulin regulates glucose metabolism.

00:01:23: So what I saw was that the insulin has fine signaling system to mediate chemical message of, you know, insulin in the cells to transduce a signal.

00:01:33: To update glucose for example and store them as glycosine.

00:01:37: so...

00:01:38: Yeah when i exercise there's a signal going on That says take glucose from your blood And put it into muscle.

00:01:47: Yes, so that's exactly what we are fascinated because in people with type two diabetes insulin system doesn't work.

00:01:54: Meaning is even you have insulin in the blood and cells they don't respond meaning communication network in the cell is actually impaired.

00:02:04: And then there're many different layers of impairments on our body.

00:02:09: We try to figure out how we can restore or change a mindset What works when insulin fails?

00:02:17: So the exercise is a solution to be able to mitigate when you have impairment in through signaling.

00:02:25: We studied from where I was PhD student with Rory Gutierre how exercises signal to regulate uptake of glucose in muscle independent of insulin.

00:02:36: and as a course of study, when i got independent we identified key enzymes called LKB-I which were only known as a tumor suppressor.

00:02:46: However, this turned out to be a regulator of exercise mediated glucose subtake through an enzyme called AMP-activate protein kinase which is our energy fuel irrigation antibody.

00:02:58: So during exercise your energy goes down repeat and then that's trigger the activation of the enzyme.

00:03:04: And in this LKB one system actually it helping for NpK to get activated and then transduce glucose sub take In the absence of insulin almost

00:03:13: So you need to do exercise, to draw the glucose from your blood.

00:03:18: That's why people who did lots of exercises don't have type two because their exercise is in effect modulating or keeping in check the glucose in their blood.

00:03:33: but if you've got type two and you're not exercising perhaps cause you can't exercise then that's not happening.

00:03:41: for

00:03:42: Yes, so that depends on the medical condition.

00:03:46: So largely when you have heart disease type two diabetes and then people patients are not fit enough to be able to exercise as much like they want.

00:03:56: however even moderate exercises is able to stimulate and peak your system to update glucose.

00:04:03: obese and also severe condition, you cannot exercise.

00:04:06: So we also demonstrate that by small molecule MPK can be activated And then without doing exercise That will facilitate glucose uptake muscle in a short term.

00:04:18: so that's a tremendously important finding because it is potentially A way of taking out glucose from the blood for people who cannot do any exercise.

00:04:31: Yeah,

00:04:31: it's very attractive because its mimic part of the exercise effect.

00:04:34: However think about you know our actually body needs to keep a balance.

00:04:39: meaning is that we just cannot update glucose forever Because glucose has to go somewhere and then if you have lots of glucose in your body And eat you also up toxic to her body.

00:04:50: So you need to burn this glucose by exercise to be able to maintain our energy balance so You can temporarily store glucose by stimulating NPKs.

00:05:00: However, exercise is still needed.

00:05:02: So also if you use a drug for long-long time and then that causes unwanted effect For example as I mentioned build up of glucose in the muscle or heart And trigger some unwanted dysfunction of cardiac system It's very important.

00:05:22: where do you activate this MPK system in your body?

00:05:25: How to do it?

00:05:36: That's fascinating.

00:05:38: So the time of day is important?

00:05:48: That's kind of

00:05:58: Julian Ziraths research, isn't it?

00:06:02: Famously the time of day that you exercise has a big impact.

00:06:06: So where do you think this research will take companies within the next five to ten years?

00:06:15: I thought we have multitude targets so NPK system is one important target.

00:06:22: So MPK and there are different family members meaning something called isopome so it's not a single actually person, It has twelve are friends, actually in our body.

00:06:33: So each individual molecule has different functions in the body so that we try to target specific MPK family member too you know actually elicit wanted effects but not unwanted effect.

00:06:47: We do molecular research to find how we can specifically target one family members of MPK and other families also how they deliver drugs for specific tissues like liver muscle and then not hitting cardiac system, for example.

00:07:03: So these are key aspects of our translational research to understand the molecular basis how we can target different tissues and what family member that we can also regulate in a body?

00:07:14: I mean there's an extraordinary amount of redundancy on the bodies isn't it?

00:07:17: but as you'd expect from such important systems

00:07:21: And here

00:07:21: you are discover something nobody knew about at all which is astonishing because we've lived with, you know... We have known about diabetes for so long and yet were still relatively ignorant of some basic mechanisms.

00:07:41: Yes, so I think the difficulty in diabetes is as you know that it's a very heterogeneous.

00:07:46: So its not single cause, its multitude of different causes through genetics and environmental factors... ...so each patient will actually elicit different types of symptoms.

00:07:57: Different tissues organs also people respond differently to the drug as well.

00:08:03: It is important we understand different molecular mechanisms in our body And then how can restore dysfunction through a particular drug, for example.

00:08:14: So I think our research and meta-research is very important to provide such molecular basis on the new generation of drugs

00:08:21: And what this also illustrates with me how important fundamental research is.

00:08:26: The basic cell biology really delivers but it takes a long time But you know, it's going to have extraordinary impact which is why of course You've been given this never-nought discord for Impact.

00:08:41: Exactly so I think there's no shortcut So that the people feel a you know transition comes in or very short time period sometime through innovation.

00:08:50: However if we look at history and then major discovery took you know twenty or thirty years.

00:08:54: sometimes If you trace back, you know The initial stages of fundamental research?

00:08:59: So i think We need keep keeping mind the basic body system, how things work in a mechanistic way.

00:09:07: And then you know how to potentially modulate our systems and be able to control them keeping their balance.

00:09:14: So maybe this drug may work well but it might not be the case.

00:09:19: so we need different layers of basic study.

00:09:29: It's

00:09:30: fascinating stuff.

00:09:32: Thank you so much for coming in to explain it, and if you want to watch this – I very much advise you do that!

00:09:41: You can of course see it in person but also find the lecture is on the EISD portal And its bye-for now.

00:09:51: thank again congratulations.

00:09:54: Diabetes, insights breakthroughs and innovators.

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