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returns. Welcome

1:34

everybody

1:42

to another episode of Dr. Matt and Dr. Mike's

1:45

medical podcast. I'm your host, Dr.

1:47

Mike Todorovic, joined by my co-host, Dr. Matthew

1:49

Barton. Matt, how are thou?

1:51

Very good, thou? Oh, no. Don't

1:53

think you've read enough Shakespeare.

1:56

Yeah, well, that's true. Shakespeare?

2:00

Yeah. What? Fiddle on the roof.

2:05

That's Shakespeare. Can you quote any Shakespeare?

2:11

Something from... What about

2:14

anything from romantic... Okay

2:16

go. Oh no. Okay. What

2:18

about to be or not to be? I know

2:20

that. You know to be or not to be?

2:22

I was gonna say that. To be or not

2:24

to be? That's it.

2:27

That is the question. That

2:29

is a question. Whether it is nobler in the mind

2:31

to suffer the slings and arrows of that... Did you

2:33

say it at school? No

2:36

I just read it. Okay. I did. I

2:38

read it. I read it as an adult.

2:40

Is it hard going? Yeah. I don't understand

2:42

20% of

2:44

it. It's brilliantly

2:47

written. I mean if you put it in the context of what was

2:49

it 1600 17th century and he made words up that are currently...

2:56

If you look at the amount of words

2:58

that William Shakespeare made up, it's

3:01

like I think it's dozens that

3:03

we currently use in just

3:05

everyday language. He was amazing

3:07

and the stories that he wrote too have

3:10

just been continually perpetuated in pretty much every

3:13

movie trope you can think of. So it's

3:15

awesome. But the language I

3:17

find difficult to understand. Do you think that

3:19

was the height and level

3:22

of English? No. As in

3:24

you think it's going down since then? No. No. I just

3:26

mean like as a

3:28

language and what he

3:30

produced. Yeah. As that you know

3:33

the literature. It was

3:35

English as a language was kind of at its

3:37

peak grammatically and you

3:40

know. No I don't think so because they would

3:42

have had their slang at the time which just

3:44

sounds fancy to us now. But I think... So

3:46

you don't think in a language? No. The purpose

3:48

of language is economy of words. It's about getting

3:51

a point across. It's

3:53

communication. So if you can

3:55

communicate with somebody using two

3:58

noises as opposed to 15... noises,

4:01

then that's economy of words. That's more efficient. That's

4:03

a better way to communicate. It depends on how

4:06

you look at it. Well, I mean, I think

4:08

there's a lot of utility or mind my language,

4:10

but there's a lot of wank associated with having

4:12

to talk with the

4:14

most eloquent and detailed terminology

4:17

in the largest word and the most

4:19

difficult words to comprehend. But if

4:21

somebody doesn't understand it, then

4:23

the whole point of the language has

4:25

disappeared. That's true. So that's why I

4:28

think it's okay to say, Hey, Matty,

4:30

how you going? And you say, good

4:33

choice. Choice. Sweet as.

4:36

All right. How have you been? Not bad. We're

4:38

talking about fasting state today. Did you know that? Yes.

4:41

I knew it was coming up because we

4:43

had done the fed state. Yes. This episode

4:45

like the, and I prepared for it cause

4:47

I've eaten for two weeks. Wow. So you're

4:49

in not just a fasting state, you're in

4:51

a starvation state. When does it become starvation?

4:54

Yeah, I don't know. I don't know if

4:56

there's a delineation. Is there a biochemical delineation

4:58

or is it just the situation? It's

5:01

just terminology. I think someone would say fasting,

5:03

I'm not going, I'm going to have food

5:05

for a period of fasting or I

5:08

can't find food. Well, I would say that

5:10

fasting is just absence of food.

5:13

And so you could fast for a

5:15

year. I'm not saying anyone should, but I'm just

5:17

saying that you could, you could say 12 months

5:20

of fasting starvation is probably

5:22

a mode of physiological state

5:26

in which probably could be classified by

5:28

certain. Or is it just access to

5:30

resources? Uh,

5:32

yeah, it could be that too. I dunno.

5:34

Maybe we should figure the answer

5:36

out before we discuss it. But,

5:38

um, no, no, this week, just

5:40

like the other episode on fed

5:42

state, this week on fasting is,

5:44

uh, brought to the dear listener

5:46

by the biochemistry, the biochemical society,

5:48

I should say, um, who have,

5:50

uh, provided us with United Kingdom,

5:52

some funding in order to produce

5:54

a couple of these biochemistry based

5:56

episodes. Uh, and you also

5:59

presented to a biochemistry. All right,

6:01

yeah, Biochemistry organization. I

6:03

presented on Friday last week, so this

6:05

time last week, not this time, but

6:08

last week. Yeah, what time was it?

6:11

Well, when they asked me, so I got

6:13

an email from the

6:16

president, I believe, of the

6:18

Biochemistry, so I think it's

6:20

called the Association of Biochemistry

6:22

Educators in the United States.

6:25

And I got asked by email, would love for you

6:27

to be our plenary for the

6:29

conference. So that's the main

6:32

speaker, which is brilliant. It's

6:34

an honor. It's really nice. And you

6:36

say yes to these things, and it's

6:38

virtual, so it's online. And

6:40

I didn't even think about the time difference from

6:42

Australia to the US, which is pretty much just

6:45

the opposing time of the day. That's

6:48

all about difference. Yeah, so what

6:50

it ended up being was, she

6:53

said, well, the conference begins at 1pm. That's when

6:56

you present. And I

6:59

go, yeah, 1pm, no trouble. Didn't even think

7:01

about Australia. And then as I got closer,

7:03

I found out that this was 2.30am on

7:06

Friday, which

7:08

is a tricky time to do a presentation, because

7:10

it's the middle of the

7:13

night. Yeah. Like when you get up in the

7:15

middle of the night and put the television on, and

7:17

there's just these weird random television

7:19

shows. You were like that, basically.

7:22

Yeah, pretty much. I was that person that they were watching.

7:25

But it wasn't middle of the night for them. So anyway, I had

7:27

to- Did you sell anything? No, I

7:29

wasn't, it wasn't like, was it the Dallas Direct?

7:31

It's just like, look at this, this necklace usually

7:33

sells for two and a half thousand dollars. But

7:35

today you can get it for $9.99 if you

7:38

call it the details now. So

7:45

it was 2.30 in the morning. I

7:47

woke up, I put my alarm

7:50

for 2am, because I was just going to wake

7:52

up and just roll out of bed and present.

7:55

But I woke up at 1 and couldn't

7:58

go back to sleep. I didn't even get any.

8:01

I didn't even get any. You didn't need the alarm.

8:03

No, I didn't need the alarm. You're like Kramer. So

8:05

I had to get everything sorted and the presentation went

8:07

very well. I did a friend

8:09

of mine in the US who's

8:12

a comedian and a magician in

8:14

Vegas, Mattie McDonoughly. He was there.

8:17

He's actually been on the podcast before by the way. He has actually. We

8:19

did an alcohol episode with him. I,

8:22

because he's a performer,

8:24

so he knows how to sort of break the ice

8:26

with an audience. And I said to him, you know,

8:28

what's the best way to start a presentation? And he

8:31

said, the best way to start a presentation is

8:33

by picking something that's relevant about the room or

8:35

the place or the time and

8:37

making an seemingly off the

8:39

cuff joke about it. And

8:41

then everyone gets comfortable and then you can talk about

8:43

whatever you talk about. So when I entered, I said

8:46

that I said, look, thank you, everybody,

8:48

for having me. Kim, the organizer,

8:50

said to me, asked me, would

8:52

you like to present and be our plenary? It would

8:54

be an honor. And I said, that would be great,

8:56

but I've got one condition. That condition is it needs

8:58

to be early in the morning because I'm a morning

9:00

person. And she said, yeah, not a problem. And

9:03

she stuck to her guns and made it two thirty in

9:05

the morning. So and that was

9:07

good. Everyone laughed. Everyone said, this is great.

9:09

And then half the people logged off. But

9:12

anyway, it went well. How have you been?

9:14

You asked that. Okay, good. Should we get

9:17

started? Let's get started. All right. I

9:19

think we should get started. Fasting state metabolism. Give

9:22

us before we go into the weeds and the

9:24

nitty gritty, give us an overview. Do

9:26

weeds provide nutrients to break you

9:29

out of the fast weeds or

9:31

weed? They'll make him hungry. Very

9:33

true. So then soon be back into a

9:36

fed state. But we're talking about

9:38

fasting. What's

9:40

the. Generally

9:42

speaking, in the fed state,

9:44

you've just eaten. Right. Very

9:46

good. And we said that in the

9:49

fed state, because you're you've saturated the

9:51

bloodstream with glucose and let's focus on

9:53

glucose as the main nutrient in this

9:55

case. But we'll talk about others because

9:57

you've the systems. flooded

10:00

with glucose and your blood glucose is

10:02

high, it goes above

10:04

the normal euglycemic level. So the

10:07

homoesthetic range, which is between four

10:09

to six millimoles per

10:11

liter. How much is that

10:13

in teaspoons? Oh, okay. Wow, really

10:15

jumped the gun there. I

10:18

thought that it would be good to put this

10:20

into context because four to five millimoles per liter

10:22

makes no sense, unless you're within medicine. Or

10:25

a chemist. Or a chemist, true, probably predominantly

10:27

chemistry. I don't think a lot of medicos would say what

10:29

it means either. So let's take the

10:31

middle of that five millimoles per liter of

10:34

glucose, so of per liter of blood. That's

10:36

equivalent to about 0.22 teaspoons

10:39

of glucose, not tablespoon, teaspoon, 0.22.

10:42

And because you get about five liters of blood in your body, you

10:45

could say that five millimoles per liter

10:48

is equivalent to a heaped teaspoon

10:50

of glucose within all the

10:52

blood of your body. So if you take

10:55

all the glucose floating through the blood in your body, Right

10:57

now. So if you're at a normal

10:59

level, at the euglycemic level, Let's say five millimoles. It's

11:01

a heaped teaspoon. Oh, not much. About, no, not much.

11:03

So when you eat the meal in the fence state,

11:05

like we spoke about the other week, your

11:08

blood glucose level can double that. You can have

11:10

two heaped teaspoons, right? You can go up to

11:12

10 millimoles per liter. And

11:14

that increase will stimulate responses that

11:16

try to drop it back down.

11:19

So, in some relief. Specifically

11:22

insulin. Glucose jumps into tissues.

11:24

And that glucose will be utilized to make

11:27

energy. And then once we've got

11:29

enough energy, the rest will be stored as

11:31

glycogen or fatty acid. For another

11:33

day. For another day. But

11:35

in this case. And this is the other day. And

11:38

exactly. But now we are

11:41

three to four hours post eating. Post-prandial.

11:43

That's fair, yep. And any time after

11:46

that, and our blood glucose levels

11:48

have now started to fall. So

11:50

what would you say broadly, like I just covered

11:52

with the fence state, how would you sort

11:54

of define the fasting state broadly before we go

11:57

into the details? Yeah, that's fine.

12:00

Well, just low blood glucose. Yeah. Oh,

12:02

OK. Nothing else. Well, fast in. Just

12:04

20 mil. What

12:08

happens in the fasting stage is to boost

12:10

blood glucose. Correct. And this is going to

12:13

be mediated by glucagon and other hormones. Yep.

12:15

But also, the main job of this whole

12:17

thing is just to boost that blood glucose

12:19

back up. Well, yes.

12:21

So I think the main player in

12:24

doing this is the liver. And

12:26

the liver is just doing that for two

12:28

other, predominantly two other organs, just to keep

12:30

the glucose in the blood. Because

12:33

two other organs really

12:35

want to keep using glucose for their energy

12:37

metabolism. And that's the brain and the red

12:39

blood cells. So those

12:41

two organs in a fasting state still

12:44

would prefer to have glucose as its

12:46

primary energy source, meaning to make its

12:49

ATP. Yeah. Well, there's a couple of

12:51

neurons, like you said, brain. The

12:54

lens of the eye and retina love glucose

12:56

as a primary energy source. The lens. The

12:59

lens, yeah. OK, well. Yeah. I wonder

13:01

if the lens really has any cells. That's

13:03

what I read in an article. No, the cornea. Article.

13:06

It said lens. Wow. I thought that was just a.

13:08

Yeah. I thought it was just a pathalia. Right?

13:12

Anyway. And

13:14

red blood cells. Called retina. I thought it was retina.

13:17

Well, it's retina as well. Lens and retina

13:19

is what it says. Retina makes sense because it's very

13:21

energy dependent. Yeah. Neurons. Let's

13:23

just say eye. Red

13:26

blood cells and renal medulla. The

13:29

major muscle requires glucose significantly.

13:31

But they're the major ones. When you say

13:33

renal medulla, you just mean the nephron cells.

13:38

That's probably what it's referring to.

13:40

Which is interesting. It says renal medulla

13:42

cells. That's what the

13:45

mission says. Just the medulla of the

13:47

kidneys, which is mostly

13:52

the nephrons. Yeah. I think there'd be

13:54

other interstitial tissue. Yeah. All

13:56

right. But the point is there's a couple of

13:58

tissues that just won't go. glucose. The brain

14:00

being one of them and red blood cells

14:03

being another. That's a big take

14:05

home point. Because red blood cells don't

14:07

have any organelles. So

14:09

they really can't do, they can't really

14:11

use many other intermediates

14:13

besides glucose just to

14:16

do glycolysis. And

14:18

we spoke about this before, but

14:22

you know, why does the brain want glucose when

14:24

it could be used fatty acids? I know that

14:26

they can't get fatty acids because it's kind of

14:28

locked out of the... What do

14:30

you mean? Well, fatty acids, do

14:33

we want to mention this now or we can get to fatty acids?

14:35

I think we can just... Oh,

14:37

okay. I think we can... Leave

14:39

it. glucose,

14:41

why doesn't it use other energy sources? So when

14:43

fatty acids are liberated from fat cells, they

14:46

aren't just released raw

14:49

into the blood. So

14:52

they're just not like... Yeah, they're just raw in the blood.

14:54

You're right. That's the way of

14:56

describing it. It's not like this

14:58

fat is spilling over into the blood

15:00

and making your blood just like olive

15:02

oil. It

15:05

has to get carried on a protein. And

15:07

this protein albumin, predominantly, I'm sure there's

15:09

others, but albumin is carrying

15:11

around the body for other tissue to use

15:13

in a fasting state like the liver and

15:16

muscles. But that

15:18

protein can't offload it through

15:20

the blood-brain barrier. Yeah. So that

15:23

means the fatty acids aren't being able

15:25

to be utilized. Yeah, they can't cross

15:27

the blood-brain barrier very well. So that's one reason why the

15:29

brain doesn't use fatty acids. The other is it can

15:32

produce relatively large amounts

15:34

of oxidative stresses, which is not

15:36

good for the brain. It's very

15:39

sensitive to oxidative stress, hence why

15:41

neurodegenerative diseases like dementia and Parkinson's

15:43

disease are strongly associated with oxidative

15:45

stress. And the

15:47

other one is that glucose is just a

15:49

really fast way to get energy. And the

15:51

brain is fast. Mine is yours is a

15:53

bit slower, a bit sluggish. You

15:55

know, you're not as smart. I get it. I get it.

15:58

I get it. You didn't have to spell that out. did

16:00

because your brain's not that good. Right,

16:04

so we got that? Yep. Now what? Well

16:06

okay well I'm gonna tell you a

16:08

story. Oh cool. Can I tell you

16:10

a story? Yeah is it relevant? It's

16:12

relevant, it's about fasting. Okay. It's about

16:14

a fast that probably wasn't intended. Right.

16:17

Okay so when I was working in

16:20

America, occasionally

16:24

at night I would work, here

16:26

we go, as I, as

16:30

I what? No I

16:32

would sometimes work on, because

16:34

I worked in America at

16:37

a ski resort. I

16:39

don't know what you were doing. But at night

16:41

you were. Night

16:43

skiing I'd work on chairlift. Now

16:46

have you been on a chairlift before skiing? I've never

16:48

been skiing. Oh never, okay. So I'm

16:50

not gonna explain what a chairlift is right? You

16:52

know what it is? Yeah. Okay. I think every

16:54

human being knows. And if they didn't, I

16:57

think the two words put together make sense. Okay

16:59

so anyway usually what it involves

17:02

is a person, a person at the bottom of

17:04

the list and the person at the top of

17:06

the list. As in working out? Working out. Yeah.

17:08

So it's obviously cold. So the person at the

17:10

top stays in a little hut. Okay

17:12

and because it's night and it's cold, usually

17:14

you feel tired. So you have to keep

17:16

yourself away. Now. Is there a heater in

17:19

there? It's a heater but it sometimes makes

17:21

it worse because you get more tired. Yeah.

17:23

So anyway this, this guy

17:25

gave me a book to read. Okay. And

17:27

it was a biography of this guy called

17:30

Aaron Ralston. Oh yeah. You probably haven't heard

17:32

of him. Because it's a very rare

17:34

book. Oh okay. Biography. Anyway

17:38

let me get into it. Okay okay. So this particular

17:41

guy called Aaron Ralston. Yep, heard of him. Very

17:43

famous. He

17:46

was a famous mountaineer. Yes. I

17:48

saw his famous now. Yeah

17:51

but you don't know any mountaineers. I don't

17:53

think he was a famous mountaineer at

17:55

the time. I

17:58

think he was just a mountaineer. Proclaim

18:00

that near I think you were famous

18:02

because he was famous in the small

18:04

community of Mountaineers. Oh, okay, then so

18:07

he Anyway, let

18:09

me cut to the chase in 2000

18:12

well, first of all, I have to be accurate

18:14

with my geography. Yes, because we've been reprimanded

18:17

by we're not good at knowing our

18:19

United States by a actually

18:21

professor in Ottawa, which is in Canada, Michael

18:24

Oh, thank you. Okay. So anyway, I'm gonna

18:26

be accurate with the what did they say?

18:28

They said our geographies

18:30

poor Particularly

18:33

particularly of North America. Yeah, they

18:36

said basically we think everything's above the

18:38

Arctic Arctic Circle is

18:40

it no? Anyway,

18:42

this particular guy Aaron in 2003 he went

18:45

Canyon in now So

18:49

I think he resided in Colorado.

18:51

Yeah, so the next date across if

18:53

you go west Thanks to water to

18:56

Colorado Utah, Utah. Yeah, so he's in

18:58

the Blue John Canyon, which is Under

19:01

the way the Wayne County

19:05

Area of Utah and that's me Blue

19:07

John. It's in one Blue

19:09

John Canyon was in the way the Wayne

19:11

County now this

19:13

is in a unit of Canyons

19:16

called the horseshoe Canyon of

19:18

Canyon land National Park in Utah Does

19:21

any of this matter to the I'm

19:23

just being geographically accurate. All right So

19:26

he was Canyon in not exactly sure what

19:29

that entails it means he just hang by

19:31

rope and swing from one side to the

19:33

other and He

19:36

was moving down the canyon

19:42

And it fell with him and as

19:44

he was falling down the canyon obviously the canyon gets

19:47

Narrow and he's right

19:49

arm got stuck between the boulder

19:52

and the wall Yes, and I'm not sure

19:54

how you heard of this and he crushed

19:56

his hand. Yes. It's a famous story and

19:58

it's a movie called a hundred hundred twenty

20:00

seven hours. Seven. One hundred twenty

20:02

seven hours. Yeah. That's not that

20:04

famous. I can't remember it. But too many hours. But

20:06

yes, hundred twenty seven hours. James Franco played the character.

20:08

Is he the guy of Spider-Man? He

20:11

was the guy of the first Spider-Man. He played

20:13

Green Goblin's son. Son. That's

20:15

right. Yeah. Spider-Man's best

20:17

friend. Yep. Yep. Okay.

20:21

I think I've watched that movie. So anyway,

20:23

he got stuck there for that many hours.

20:25

Which is like five days. Yeah.

20:27

So he had a bottle of water. I

20:31

think some burritos, maybe an energy

20:33

bar. Okay. But then he ran out of that.

20:36

And he went through periods of saying, oh, there's

20:39

no way I'm getting out of this. I

20:41

think he then hallucinated.

20:45

And he was, I think

20:47

he'd done his final goodbye video.

20:50

Okay. Did he make a

20:52

video? Yeah, he made a video. Oh yeah. It's

20:54

in the movie. And he thought this is it.

20:56

Yep. The

20:59

rock wall, my name, date of birth,

21:01

when I'm about to die. Yep. But

21:04

then that night he hallucinated. And

21:06

the dream that he had was him

21:09

with his child and

21:12

himself missing an arm.

21:15

Wow. And I'm not sure

21:17

if you had some kind of prosthetic. Okay.

21:21

But he thought that was something

21:24

to kind of go, well, maybe I should take my

21:26

arm off. And so the next morning he, because

21:29

he'd already attempted to try to take it off, and he

21:31

only had like a small kind of pocket

21:33

knife. Yep. And he thought this was

21:35

on the, never going to get through the bone with this. Yeah. So

21:38

the next morning he thought, oh, what I can do is use the

21:41

wall and the boulder as a

21:43

vice and just swing out and break, snap

21:45

it, and then cut through the skin,

21:48

the muscle with a knife. But I think when he

21:51

got to the tendons and

21:53

the, it's a bit tricky. It's

21:55

hard to cut. Yeah. And sometimes hard to

21:57

cut a steak with a steak knife, let alone your arm

21:59

with the little pocket knife. It would

22:02

have been rough. So tourniquade with the Camel Pack.

22:04

Yeah. So what's this got to do with the...

22:06

Anyway, this is just an example of in this

22:08

situation, he was obviously fasting because he was running

22:11

out of it. Oh, so it helps. One

22:14

of the benefits of fasting. Let's cut your arm

22:16

off. I get it now. This is the benefit

22:18

of why we have this biochemical backup system. Did

22:20

I help him in this process? Yes, he survived.

22:22

Oh, so it helped him. Yeah. How do you

22:24

know that? How do you know it was fasting

22:26

that helped him? Not the

22:29

fasting, but the biochemical fasting

22:32

state of what you

22:34

can do without the abundance of

22:36

glucose anymore. To keep yourself going

22:38

over hours, days,

22:40

weeks, potentially months.

22:43

Okay. Well, that was interesting, I

22:45

suppose. In part, there was something

22:48

to it, I suppose. So with

22:50

this particular gentleman, Aaron. Yeah. No more about

22:52

him. Okay. Five days, let's just say. All

22:55

right. Without food. I know he had a

22:57

bit of food, but let's just assume that

22:59

he had no food from the get go.

23:02

So we changed the story. What is his

23:04

body doing to

23:06

maintain homeostasis? I see. Now

23:09

I see what we're doing.

23:11

Okay. Great question. Great question.

23:13

So like we said,

23:15

after three to four hours, his

23:18

body is in a fasting state. And like you said, he's there

23:20

for 127 hours, give or take. So

23:24

he's got a little way to go. Yeah. So what

23:26

is happening? Oh, so the first thing we need to

23:28

think about is that once we hit three to four

23:30

hours, blood glucose levels

23:32

drop. That's the first thing. And

23:35

we know homeostasis is about maintaining happy,

23:37

healthy balance. We spoke about

23:39

fed state where it goes too high. We try

23:41

and bring it back down using insulin, but

23:44

now it's going too low. And so this

23:46

drop in blood glucose will stimulate another hormone

23:48

to be released from the pancreas. It's not

23:51

insulin in this case, but glucagon. Okay.

23:53

So glucagon, where is

23:55

that from? That's from the pancreas. Yes, but it's

23:58

from the alpha cells, not the beta cells. cells,

24:00

but they're all sitting there within the

24:02

pancreatic islet cells. And

24:04

so once this glucagon is released, this is

24:07

really important. The glucagon is a really

24:09

important regulator within the

24:12

fasting state because

24:15

generally speaking when you've

24:17

got glucose abundantly available and

24:20

insulin's available because it stimulates the

24:22

release of insulin when you've got

24:24

enough glucose, the insulin not only

24:26

triggers glucose to enter tissues like

24:28

muscle and fat, but it

24:30

also stimulates the enzymes of glycolysis

24:33

in the Krebs cycle to undergo

24:35

those processes because when

24:37

you've got glucose and you undergo

24:39

glycolysis, you make energy either

24:42

directly or indirectly, directly by making

24:44

ATP or indirectly by making NADH.

24:47

And then when you go to the Krebs cycle, it

24:49

does the same. You will make some ATP directly or

24:51

some indirectly through NADH or FADH2. Those

24:55

NADH FADH2 molecules, they're

24:58

carriers for electrons and protons. So

25:01

if you take a hydrogen atom,

25:04

so the first atom on the periodic table, it

25:06

is made up of one positive charge

25:08

called a proton and one negative charge

25:10

called an electron flying around the outside.

25:13

Because they balance each other out, a hydrogen atom is neutral.

25:15

It's just H. But

25:19

what we do with the glycolysis

25:21

and the Krebs cycles, we're trying to

25:23

rearrange a six carbon molecule called

25:25

glucose in a way

25:27

that we can pull off protons and electrons. And

25:30

that's what NAD plus does and

25:32

FAD does. They pull off hydrogens.

25:34

And what are those reactions called?

25:37

They're oxidisation reactions. They oxidise these

25:39

molecules by allowing those molecules to

25:42

lose their electrons. So

25:44

NAD plus will pull hydrogen and electrons

25:46

off or at least hydrogen off, which

25:48

contains electrons. And so

25:51

does FADH FAD. They

25:53

carry the hydrogen to the electron

25:56

transport chain. Which is in the mitochondria.

25:58

That's right, the inner membrane. feed

26:00

the electrons to the

26:03

proteins and that

26:05

excites the proteins. It excites them so much

26:07

that they can then take the protons, the

26:09

hydrogen ions, the H+, because

26:11

obviously we've now pulled the negative electrons

26:13

off them, so it's just an H

26:16

with a plus left, and

26:18

it excites those proteins so much that

26:20

they pump the hydrogen up into what we

26:22

call the intermembrane space of the mitochondria, the

26:24

space between the two membranes. Now

26:27

we have a really high concentration of hydrogen ions

26:29

in the intermembrane space. High

26:31

concentration, it wants to go down its

26:34

concentration gradient, so it moves through another

26:36

protein called an ATP synthase. As

26:38

the protein moves down, that

26:41

energy spins a turbine that produces

26:43

all this ATP. The

26:45

point I'm trying to get across here is that in

26:49

the fed state, glycolysis and Krebs

26:51

cycle is noted by its energy

26:54

producing ability. Right.

26:57

But when we are in a… And

26:59

then so insulin is… And insulin is

27:01

mediating that. Yeah, yeah. But the thing is

27:04

when glucagon is high, because blood glucose levels

27:06

are low in this fasting state, it switches

27:08

off those enzymes. Yeah. So

27:10

we don't make ATP. And

27:13

you might think, wait a minute, but we're fasting. Don't

27:15

we want to make ATP? But the point

27:17

is that at the moment, all it

27:19

cares about is remedying the

27:22

blood glucose levels. Mm-hmm. Or

27:24

the liver. The liver is… The liver. Yeah.

27:27

Yes, yes, yes, exactly right. Sorry. We're focusing

27:29

here on the liver. It's the liver that's

27:31

trying to fix the low blood glucose levels.

27:33

The problem. Yeah. And so it does this

27:35

by having the pancreas

27:37

release glucagon. When

27:40

we look at this whole process,

27:42

it wants to make glucose. So if you look at

27:44

how can we make glucose, we go,

27:46

okay, there's one easy way we can do it. We

27:49

stored excess glucose as glycogen. Yeah.

27:52

And that process goes glucose to

27:54

glucose 6-phosphate. Glucose 6-phosphate

27:57

shoots off the side to glucose 1-phosphate.

28:00

and glucose 1 phosphate is stored as glycogen. Now,

28:03

when glucagon is present, it

28:06

says, hey, glycogen, break up

28:08

again, go back into glucose 1 phosphate,

28:10

go back into glucose 6 phosphate, and

28:13

try and turn into glucose. The problem is,

28:16

all of that's reversible, except

28:18

the very last step. In the liver.

28:20

In the liver, going from, well, in

28:22

any tissue, basically. You can't

28:24

go from glucose 6 phosphate to glucose.

28:27

Because if it's phosphorylated

28:29

like that, you can't leave the tissue. Glucose

28:31

6 phosphate has a phosphate. You can't leave

28:33

the tissue. That's one of the reasons why

28:35

it becomes phosphorylated, right? Or has a

28:37

phosphate group, I should say, attached to it. So

28:40

we need a way to reverse glucose 6

28:42

phosphate to glucose so it can jump out

28:44

of the liver and go back into the

28:46

bloodstream to fix blood glucose. That's what glycogen

28:48

does. Glycogen switches on an enzyme that

28:51

allows for that. Not glycogen. Glucagon. What

28:54

did I say? Glycogen. Sorry. Glycogen.

28:57

Glycogen switches on

28:59

an enzyme that allows for it to

29:02

be reversible. And that enzyme is glucose

29:04

6 phosphatase. So now, with the presence

29:06

of, so when blood glucose levels are

29:08

low and glucagon levels are

29:10

high, this combination

29:13

of things tells glycogen

29:16

to start breaking up and

29:18

switches on glucose 6 phosphatase. And it

29:20

allows for glycogen to go glycogen to

29:22

glucose 6, 1 phosphate,

29:24

glucose 6 phosphate, and then to glucose and

29:26

then it can jump out of the liver

29:29

and go into the bloodstream to try and

29:31

remedy it. And this is going to be

29:33

the predominant way we fix our blood glucose

29:35

levels in a short-term state. So after an

29:37

eight-hour fast, so a nighttime fast,

29:39

you know, you go into bed, wake up in

29:41

the morning. If you haven't had a midnight snack,

29:44

it's been eight-odd hours. At

29:46

this time point, glycogen is being

29:48

used between 40 to 70% of the glycogen.

29:53

40 to 70% of the glucose being

29:55

made to fix the blood glucose levels

29:57

is coming from glycogen. So when people...

29:59

People are to compete in

30:03

events where they're going to expel a lot of

30:05

energy. We

30:08

hear these terms of carboloading,

30:12

where they have a big bowl of complex

30:14

carbohydrates and I would fall, like pasta. What

30:18

potentially that is doing is just filling

30:20

your liver up and muscle

30:23

as much as it can with glycogen because

30:25

that's the preferred energy source that you're going

30:27

to be relying on the next day when

30:29

you're competing. At least to a point that

30:31

you've burned them all off. The

30:35

first energy source you're going to go to will

30:37

be the glycogen stores. Don't

30:39

get me wrong, it's not like

30:41

it only uses glycogen. It's just the predominant.

30:45

This is just the predominant. When

30:48

it uses glycogen, predominantly but

30:51

simultaneously, it will use other sources and

30:53

we'll get to that point. Your

30:55

body can store around about 190 grams

30:57

of glycogen and you need

31:00

about 160 grams for a

31:02

day. You probably got

31:05

about 30 odd hours of glycogen. Depending

31:07

on what you're doing. Exactly. If

31:10

you're doing exercise or hard manual labor, that's

31:12

going to go well within 30 hours. For

31:16

Aaron, he has ... Who's that? Aaron.

31:19

Oh, that James Fracko. He's

31:22

been trapped. Let's just

31:24

say for approximately eight hours, half

31:26

a day, he's going to predominantly be

31:29

using glycogen as his preferred

31:31

energy source to keep his blood

31:33

glucose at a steady state. Now,

31:35

to complicate it in his case,

31:38

he's going to be a bit stressed. When

31:41

you're stressed, you release adrenaline and cortisol. These

31:44

two chemicals potentiate

31:47

glucagon. They

31:49

can support the role of glucagon, which means

31:51

they probably mobilize more glycogen

31:54

into glucose than would happen in

31:56

a normal fasting state at the

31:58

same time. So he's

32:00

probably going through his glycogen faster. Yep. And

32:03

then also like because he was in the middle

32:05

of a desert, he,

32:07

and this was definitely something

32:10

he reported upon in the book

32:12

is during the day, it's obviously nice and hot. Yeah.

32:15

But at night, it gets really cold.

32:17

And so during the night he would

32:20

speak about how completely uncomfortable it

32:22

became because I think he even wrote to

32:24

wrap around himself. It was fine to have

32:26

your arm under a rock. That was absolutely

32:29

comfortable. Anyway, so as you

32:31

would probably imagine, if you're super cold, you're

32:33

going to be shivering and so that's going

32:35

to be generating a lot of energy to

32:37

keep you warm. And so

32:39

his energy expenditure would be up. Yeah, that's

32:41

right. For that particular. So

32:44

in the early stages of fasting, the

32:47

glucose that's been made to try and fix blood glucose

32:50

levels, 40 to 70% are

32:52

coming from the stored glycogen, which are predominantly

32:54

in the liver. It's

32:58

going to be coming from the liver mostly

33:00

because even though the muscle stores glycogen, it's

33:02

selfish and keeps it to itself. So if

33:04

the muscle needs stored glycogen, it uses its

33:07

own and keeps it to itself. Yeah. And

33:09

the reason why it mobilizes its

33:11

glycogen for the whole body. The reason for

33:13

why that is, is because the muscle lacks

33:16

that last enzyme. Yes, that's right.

33:19

Glucagon will not turn it on for it.

33:21

It's just the liver and kidneys basically. And

33:24

I think you sent me a paper that said the

33:26

intestines to a degree that will switch this enzyme on.

33:29

So this is what

33:31

is this actually called? This has got glycogenolysis? This is

33:33

called glycogenolysis. Okay. And

33:36

so just to reiterate, the

33:38

liver is doing this. Yep.

33:41

It's pumping glycogen, sorry, it's breaking down

33:43

glycogen, pumping glucose out to the body.

33:46

Yep. So is the kidney? Yep.

33:49

Have you got numbers on? The kidney is like the last one to

33:51

do it. The kidney is sort of like the last organ

33:55

to mobilize glycogen to glucose.

33:57

Okay. And then the muscle is

33:59

also breaking down. glycogen but

34:01

it just can't release it and

34:05

got that last enzyme step.

34:07

So that just becomes oxidized

34:10

into ATP through glycolysis. That's

34:12

right. Okay. All right now.

34:14

Do you want me to, are you done with glycogen? Yes. Okay.

34:17

Do you want me to quickly just mention a couple of disorders or you prefer

34:19

not? No, let's do all the disorders at the end.

34:21

Okay. If that's okay. Sure.

34:25

So as the time goes on, right,

34:27

you go from eight hours to let's say 14 hours,

34:29

the role of

34:32

glycogen breaking down to release glucose

34:34

becomes less and less and less

34:37

and it starts to become more

34:39

reliant upon other sources. Now

34:41

these other sources are non

34:43

carbohydrate based which means they

34:46

aren't any products that

34:48

you'll see within glycolysis or the

34:50

Krebs cycle. They come from outside

34:52

of these processes and

34:55

generally they're non-hexose based

34:57

or they're non-six carbon

34:59

molecules, right? They're non

35:01

carbohydrates and there's

35:03

a couple of different types of what

35:06

we call gluconeogenic substrates.

35:08

Okay. What's that

35:10

word mean? So if you break it up, glucone

35:12

means glucose, neo means new, genesis means the beginning

35:15

of and if you read it backwards,

35:17

it's the beginning of new glucose. Okay. And

35:19

so that's what it's trying to produce new glucose. So

35:21

what we've done so far. And again, this is just

35:23

liver. Yes. What we've

35:25

done so far is a produced old glucose

35:28

because glycogen was glucose to begin with,

35:30

but these substrates, they weren't glucone.

35:34

And just to mention it

35:36

at the front end, these are lactate, glycerol

35:40

and amino acids. Okay. So

35:43

lactate comes from anaerobic respiration. Yes.

35:46

And that's predominantly from muscle and red

35:48

blood cell sources. Yeah. What

35:51

was the second one? Glycerol.

35:53

That's a backbone for storing

35:55

fat. Yeah. The triglycerides.

35:58

Yeah. And the third one. amino acids

36:00

and that's the golden blocks of

36:03

protein. Yes. Can

36:05

we start with lactate? Yep, sure.

36:07

All right. So

36:09

if we start with muscle, we

36:11

know that when muscle

36:14

contracts, it requires ATP

36:16

for the cross

36:18

bridge linking and so forth. So it needs

36:20

ATP. The

36:22

glucose it currently has, it will

36:25

turn into ATP and ADH through

36:27

glycolysis, but then it can feed

36:29

to the Krebs cycle and produce

36:31

more ATP and NADH and FADH2

36:33

and then feeds the NADH and

36:35

FADH2 to the electron transport chain

36:37

to produce that ATP. One

36:40

thing we didn't mention about the electron transport chain

36:42

is that once we've produced all that

36:45

ATP, we've just got all of these

36:47

electrons and protons left over. So

36:49

the thing is, electrons, they're

36:51

damaging to tissue. We don't want them hanging around.

36:54

And protons, which are hydrogen ions,

36:57

that's acidic. So they're damaging. We need

36:59

a way to mop them up, to buffer them up.

37:02

And this is where oxygen comes into play. Oxygen

37:05

is what we call the final

37:07

electron acceptor. So oxygen will

37:09

take those electrons and take those protons

37:12

and wrap it up to produce water, H2O.

37:16

And water is innocuous. Water makes up 60%

37:18

of our, 60 to 70% of our body weight. We

37:21

have it, we love it, we need it. And

37:24

we've just taken two things that can damage us and

37:27

turn it into something that we require.

37:29

But we need oxygen to do it.

37:31

Okay. Now, if you are a muscle

37:33

tissue and you're in the gym and

37:35

you're doing crazy fast bicep curls or

37:37

you're doing sprint training, where

37:40

your muscles need a lot of ATP

37:42

to contract very quickly, you

37:44

might not have enough oxygen in the system to

37:47

be able to let the electron transport chain do

37:49

its thing. Right. So it backs

37:51

up. It backs up into

37:53

the Krebs cycle and backs ultimately up

37:55

into pyruvate, which is the final product

37:57

of glucose. Yeah. Now the thing

37:59

is, if a... So, when it backs up to pyruvate, pyruvate's

38:02

got nowhere to go because pyruvate

38:04

cannot go backwards. It's irreversible.

38:07

Yes. Which we'll speak to

38:09

later. Exactly. So pyruvate needs to turn

38:12

into something and what it turns into

38:14

is lactate. So, in

38:16

muscle, when there's not enough oxygen

38:18

to meet the energy demands called

38:20

anaerobic respiration, pyruvate turns to lactate.

38:23

Okay. So, instead of the...

38:25

Not lactic acid. Okay. So,

38:28

instead of the pyruvate normally

38:30

going into the mitochondria through

38:32

a couple of steps to make acetyl CoA, instead

38:35

because you're without oxygen, it's

38:38

making ATP into lactate.

38:41

Okay. And so, lactate will start

38:43

to build up in the muscle

38:45

if you're exercising vigorously. Correct?

38:49

Yes. It doesn't make ATP into lactate, it turns pyruvate

38:51

into lactate. Oh, that's what I meant. And

38:53

so, this lactate, is it similar

38:56

to what was happening in an electron transport

38:58

chain that it is an acid? It's...

39:02

No. So, in that case,

39:04

because we do hear that when

39:06

your muscles are exercising

39:08

vigorously, you are releasing

39:10

this byproduct, whether it's lactate or lactic

39:13

acid. And that is

39:15

causing that burning sensation. Is that true?

39:18

No. So, what

39:20

used to be said and what still is stated in

39:23

textbooks is that, exactly that, you

39:25

make lactic acid through anaerobic

39:27

respiration and lactic acid tells you

39:29

that there's going to be hydrogen

39:32

ions being released and then once the hydrogen ions

39:34

are released, you get a conjugate base, which is

39:36

the lactate. So, it goes lactic acid splits

39:39

apart to release hydrogen ions and lactate. And

39:43

then it's those hydrogen ions that make the

39:45

muscle tissue damaged and burning and less able

39:48

to contract and so forth. We

39:50

don't necessarily... There's some people who think it's still

39:52

the case. We don't necessarily think that this is

39:54

actually what's happening. What

39:56

we think happens is that pyruvate turns directly

39:59

into lactic acid. Okay. And

40:01

in doing so, it actually produces

40:03

NADH, which is a reducible

40:06

agent, which means it can be used to

40:08

make ATP, which is a great thing. Yeah.

40:11

But then the question is, well, where's

40:13

the acid coming from? Yeah. And the

40:15

answer is ATP production. When

40:18

you make ATP, you make acid. So the

40:20

thought is that because

40:22

of the NADH that comes off, which

40:24

can be utilized elsewhere, such as the

40:26

electron transport chain, for example, it

40:29

can make hydrogen ions. So

40:31

creating ATP creates hydrogen ions. Okay. So

40:34

what it's basically, it's still doing

40:36

the driving of the electron transport chain, but you

40:38

haven't got oxygen to mop it up. Potentially.

40:42

The other thing is that the

40:45

ATP doesn't necessarily come from electron

40:47

transport chain because the NADH can

40:49

be fed and used elsewhere as

40:51

an energy source, such as it

40:53

can be utilized as a substrate

40:55

to reverse glycolysis. Right?

40:58

Because we need that substrate to

41:00

reverse glycolysis. So

41:02

that's the thought. But is it fair to

41:04

assume still, regardless of what's happening, that

41:07

if you were to put a

41:09

monitor into your muscle and you

41:11

are in an anaerobic situation? It

41:13

becomes acidic. Yeah. It

41:16

becomes acidic. But it's not because of lactate. We're just not

41:18

exactly sure how. Lactate is a buffer. Lactate can actually bind

41:20

to hydrogen ions. Yeah. Okay. So

41:22

it can mop them up. So in actual

41:24

fact, we think now that lactate isn't there

41:26

as the bad guy, but lactate

41:29

is being produced because it's one way

41:31

of being able to mop up the

41:33

hydrogen ions that are being produced elsewhere.

41:35

Okay. Or by another thing.

41:37

But it could be representative that the

41:39

state there is an acidic state, but

41:41

it's not causing an acidic state. Yes,

41:45

that's right. Now, if the muscle

41:47

is producing that lactate. Because what? Just one

41:49

thing there. I came across this recently and

41:51

it just said maybe, and please

41:54

shoot this down, maybe an

41:56

evolutionary role here is,

41:58

well, if you are. are in an

42:01

anaerobic state, so you're exercising

42:03

to an extent where you are

42:05

producing lactate as the

42:07

endpoint or it's soaking up the

42:09

acid. Your muscles, because it's

42:11

becoming more aesthetic for whatever

42:13

reason, it's becoming painful

42:16

or it's just discomfort. So

42:19

you're going to dial back

42:21

your exercise intensity, which

42:24

is then going to allow oxygen to come

42:26

back in and then that can...

42:28

But we also need to remember that there's

42:30

other things that cause discomfort within the muscle

42:32

tissues such as high ATP

42:35

levels can actually stimulate

42:37

nociceptors. Protons, so

42:40

hard to announce, stimulate nociceptors. Potassium

42:42

stimulates nociceptors, all a range of

42:45

other chemicals being released. The ionic

42:48

imbalances, so electrolyte imbalances can do this

42:50

as well. So there's a lot of things,

42:52

a range of factors going into this.

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get this dinner party started. So

44:00

we said that the muscle will

44:02

take pyruvate and turn it into lactate.

44:05

But it can't do much with it in the muscle. So

44:08

it must leave the muscle, jump into the bloodstream

44:10

and then go to the liver. And

44:12

the liver will take that lactate and

44:15

turn it back into pyruvate. Now the

44:17

question is, wait a minute, if the muscle,

44:20

the muscle can take lactate and turn it

44:22

to pyruvate. But the problem is, remember

44:26

originally, we're in a

44:28

fasting state. We've got low blood glucose levels. When

44:32

low blood glucose levels are there, I

44:34

said glucagon is high. And if glucagon

44:36

is high, we inhibit glycolysis and Krebs

44:38

cycle. So we don't want pyruvate to

44:40

jump into the Krebs cycle and turn

44:42

into acetyl-CoA. So

44:46

if in the muscle, lactate can turn

44:48

into pyruvate but can't go back that

44:50

way, it can't go

44:52

forward to create acetyl-CoA in the Krebs cycle

44:54

because that's switched off from the glucagon. But

44:57

it can't go backwards because it's irreversible. What

44:59

can it do? And like I said, it jumps out,

45:01

goes to the bloodstream, goes to the liver. And

45:04

liver takes lactate, turns it to pyruvate. But you're going

45:06

to go, same problem. But the

45:08

thing is, no, not in the liver because

45:11

glucagon in the liver will

45:13

stimulate the production of an enzyme

45:15

that allows for pyruvate to turn

45:17

into something called oxaloacetate. Even

45:20

though that's in the, that's in the mitochondria.

45:23

Yes, and that's in the Krebs cycle.

45:25

So generally speaking, when you want to

45:27

make ATP or energy, oxaloacetate

45:30

needs to bond to acetyl-CoA.

45:33

And when they bind, they produce citrate and

45:35

then citrate undergoes all these... That's why it's

45:37

called the citric acetyl-CoA. Exactly. So

45:40

if you're turning pyruvate

45:42

into oxaloacetate, you

45:44

might go, but that's feeding into the Krebs

45:47

cycle. It's not because what we ultimately do

45:49

is pull the oxaloacetate out of the Krebs

45:51

cycle. Throw it out

45:53

of the mitochondria into the cytosol. Back in the

45:55

cytoplasm. That's right. We

45:57

can't do it directly because...

46:00

the structure of oxaloacetate doesn't allow it to

46:02

leave the mitochondria. So oxaloacetate turns

46:04

to malate. And that's the step before

46:06

oxaloacetate. In the Krebs cycle it is,

46:08

yes. So oxaloacetate will turn into

46:11

malate. Malate can leave

46:13

the mitochondria and then it turns

46:15

back into oxaloacetate. And

46:17

then oxaloacetate can turn

46:19

into the step before

46:21

pyruvate of glycolysis, which

46:24

is phosphoenolpyruvate. PEP. The

46:26

thing is though, we need another

46:28

enzyme to do that. And that's where, again,

46:30

glucagon comes into play. It switches another enzyme

46:33

on and allows for that

46:35

to happen. So effectively what we've done

46:37

is we've created our own little cycle

46:41

of turning lactate into pyruvate in

46:43

the liver, pyruvate into

46:46

oxaloacetate and oxaloacetate into

46:48

phosphoenolpyruvate, which is part

46:50

of the Krebs, part of the glycolytic pathway.

46:54

We want to turn this into glucose ultimately. Yeah.

46:56

Well, the liver does because the liver wants to

46:58

put it out and keep the blood sugar out.

47:01

So if we're at the level

47:03

of phosphoenolpyruvate and we go backwards

47:05

through the Krebs cycle, it must

47:07

go phosphoenolpyruvate to 2-phosphoglycerate. From

47:09

2-phosphoglycerate to 3-phosphoglycerate. From

47:11

3-phosphoglycerate to 1-3-bisphosphoglycerate. From

47:13

1-3-bisphosphoglycerate to 2-glyceraldehyde 3-phosphate.

47:15

So you're just reversing

47:17

glycolysis here. That's right.

47:19

And here, because we're

47:22

doing gluconeogenesis, the point of

47:24

this is that we're

47:27

essentially reversing the 10 steps of

47:30

glycolysis, but there are three points which you can't

47:32

reverse. Yes. So I'm getting to that. And this

47:34

is the first one we've done, which

47:37

is the malate oxaloacetate. No, no. We already

47:39

spoke about one of them at the very

47:41

top. Oh, OK. So this is... So just

47:43

let me continue this because I'll explain that.

47:46

So we're going backwards, like you

47:48

said, we're now at glycerate-hut 3-phosphate.

47:50

We're going backwards, back up now

47:52

to fructose-1,6-bisphosphate. We can go backwards

47:54

because all of these steps are

47:56

reversible. Yes. But once

47:58

we get to fructose-1,6-bisphosphate... It's irreversible

48:01

to fructose 6-phosphate. Glycogen,

48:05

glucagon stimulates another

48:07

enzyme, which is called

48:09

fructose 1, 6-bisphosphatase and

48:11

allows for it to be reversed into fructose 6-phosphate.

48:14

That gets reversed to glucose 6-phosphate.

48:17

Now remember we spoke about glycogen. When

48:19

glycogen needs to be mobilised into glucose,

48:21

it ultimately goes from glycogen to glucose

48:23

1-phosphate to glucose 6-phosphate and we said

48:26

it was irreversible to go

48:28

from glucose 6-phosphate to glucose 6-phosphate. I think this

48:30

is actually done in the past week or two.

48:33

Possibly. It's not in the site

48:35

at all. And we

48:37

said glucagon, being present

48:39

allows for that enzyme, glucose

48:42

6-phosphatase to be present to reverse it

48:44

to glucose. So effectively, if

48:46

you were to draw all this out, because

48:48

of the presence of glucagon, the

48:51

liver reverses

48:53

all the steps of glycolysis so

48:57

that lactate can turn

48:59

to pyruvate, can turn to

49:01

oxaloacetate, can turn to phosphine

49:03

or pyruvate, which is now glycolysis

49:06

and then goes backwards all the way up

49:08

to glucose, which can jump out into the

49:10

bloodstream and feed tissues like the brain and

49:12

the eye and the red blood cells. So

49:16

effectively, we've turned lactate into glucose

49:18

and that's gluconeogenesis. That's

49:21

one of the products that we can

49:24

use to make new glucose. That's one. But

49:26

the others are easy now because we've spoken

49:28

about the pathway because there are amino acids

49:30

that jump in at the exact same spot

49:33

that lactate does, like alanine. So

49:35

alanine is a good one because when you

49:37

are breaking down amino acids to

49:39

liberate, to go into the blood, to go to the liver, to

49:42

then be repackaged into glucose, alanine

49:44

is one of the most abundant amino acids

49:47

that have been liberated from the muscle. So

49:50

then this particular, this is usually

49:52

given an example, right? Alanine

49:55

as the amino acid that

49:58

can be primarily used. for gluconeogenesis

50:02

made into pyruvate. Yep. So

50:06

how does it go about reforming that? Well,

50:10

the protein will break down in the

50:12

muscle tissue and will release alanine. Alanine

50:14

can get to the liver and will jump in

50:16

and turn into pyruvate. And then same

50:19

thing, pyruvate goes to oxaloacetate which goes

50:21

to malate and then back

50:23

to oxaloacetate but then phosphine or pyruvate and all the

50:25

way back through the reverse glycolysis.

50:28

Is there anything that has to

50:30

be done differently with processing

50:33

an amino acid compared to like paper?

50:36

It depends on the amino acid.

50:38

So amino acids have amine groups

50:40

associated with them and ultimately

50:42

the amine which is NH4 plus

50:45

is ammonia based and

50:47

that's damaging to the body. So

50:50

the amino acids need to be processed in a

50:52

particular way and ultimately the amine

50:55

group needs to be sent to

50:57

the urea cycle so

51:00

it can be gotten rid of. But

51:02

effectively alanine just jumps into pyruvate. Okay. But

51:05

then you got other amino acids that can

51:07

jump into other spots like glutamate can jump

51:09

into alpha-ketoglutarate which is part of the Krebs

51:11

cycle and pretty much, I

51:14

think it was you that told me this,

51:16

nearly every amino acid can jump into these

51:19

metabolic processes except two,

51:21

right? So

51:23

there's 20 amino acids if

51:26

you want to simplify it. So

51:29

all proteins are made up of amino

51:32

acids. Amino acids are like the alphabet

51:34

or the protein that makes the protein

51:36

different and the,

51:39

I guess you'd say the R group is the

51:41

uniqueness of the amino acid, right?

51:45

It gives it flavoring characteristics. So

51:47

18 of the amino

51:49

acids out of the 20 can

51:51

be fed into all

51:53

these kind of steps, pyruvate all

51:56

the Krebs cycle to make

51:58

intermediates. And

52:00

some can be what we call glucogenic,

52:03

which means... Or gluconeogenic. Or

52:05

making glucose or ketogenic, which

52:08

makes ketones. Or both. Or

52:10

both. Or none. Or none.

52:12

And there's two that can't

52:14

be used for gluconeogenesis, and

52:16

that's leucine lysine.

52:19

Okay. Now, you can have glutamine

52:22

and glutamate, jumping down for ketoglutarate. You

52:25

can have serine, glycine, threonine. That can

52:27

be thrown in at pyruvate as well.

52:29

Serine and glycine can jump

52:31

in higher up within glycolysis. But the point is

52:33

that amino acids can be used to make glucose.

52:35

That's the point. And

52:38

that... Their term would be glucogenic? Gluconeogenic.

52:41

Gluconeogenic. And so they

52:43

are essentially amino acids that will

52:45

either go directly into pururvate or

52:48

into oxalacetate. Yes. And then do

52:50

what you just spoke about, is reverse

52:52

glycolysis. That's right. Yep. So

52:55

right now we've spoken about lactate, and we've spoken

52:57

about amino acids. The final...

52:59

The additional thing just to say with... We

53:02

spoke about cortisol being

53:04

a stress hormone, and we know cortisol

53:09

is like a glucocorticoid. And

53:12

if we use it synthetically, you know,

53:15

if you want to use it for, say, an anti-inflammatory

53:18

agent, or if you

53:20

want to use it as an immune suppressor, commonly

53:24

it would be used as a topical agent,

53:26

so cortisone or hydrocortisone. They put it on

53:28

your skin when you have conditions like dermatitis.

53:32

Yep. But a side effect

53:34

of it, it is

53:36

catabolic. I don't think that's a term. Catabolic.

53:39

Catabolic. Specifically the protein. So it

53:41

breaks down protein. So

53:43

if you were to put on your skin a lot,

53:45

you'd actually get thin skin because you're... It's

53:48

breaking down protein. Which you've already got.

53:50

Yeah. And so the point

53:52

I'm making here is when you're releasing

53:54

cortisol in a stress

53:56

situation, during your fast, as

53:59

Aaron would be in... Yes, it would be

54:01

breaking protein broken protein. So you're going

54:03

to get a liberation a lot more

54:05

proteins. Yes for the energy exactly now

54:08

the final gluconeogenic substrate is

54:11

Taking it triglycerides so fats

54:15

and you said earlier that triglycerides are made

54:17

up of glycerol and fatty acids through fatty

54:19

acids Three fatty acids are trying this role.

54:21

Yep So like you said

54:23

glycerol is the backbone so you can take the

54:25

triglycerides and split them apart and what's

54:27

that called? It's called lipolysis.

54:30

Yeah, and you can free the glycerol itself.

54:32

And so to do that's happening in fat

54:34

cells It's happening in

54:36

fat cells. Yeah adipocytes adipocytes now

54:40

To do that. It's obviously needing an

54:42

enzyme. Okay, and what would that enzyme

54:44

be called? I like the lytic enzyme

54:46

What is it? Homos a hormone sensitive

54:48

one? Okay, and so the hormones during

54:50

this date? Yeah would be those three

54:52

glucagon Cortisol and noradrenaline

54:54

correct. Yeah, that's called a hormone

54:56

sensitive Lipase. Lipase.

54:59

Yeah. Okay. And if you remember when we

55:01

did the fed state We spoke about lipolytes

55:03

in the endothelium. There was an there was

55:05

an enzyme that broke the veal deals up

55:07

Yeah to get the fat into

55:09

the fat cell to be repackaged up, but

55:11

this is doing the reverse Yes, so this

55:13

hormone sensitive lipase is Which

55:16

has been turned on it will be turned off

55:18

by insulin, but it would be turned

55:20

on by those three So when you are in that

55:23

fast in glucagon Stress

55:26

say noradrenaline cortisol

55:28

then this enzyme is working.

55:30

Yes You

55:32

know hard to be just

55:35

liberating all these fatty acids and glycerol into

55:37

the blood Yes, and you're right that insulin

55:39

is a very strong negative regulator of this

55:42

So if you have any level

55:44

of insulin being released, it will

55:46

stop lipolysis and that's important It's

55:48

important when it comes to diabetics and

55:50

we can probably touch upon that shortly So

55:53

we've we've broken down triglycerides

55:55

and we've liberated some glycerol

55:58

the glycerol can jump in to

56:01

a part of

56:03

the glycolytic pathway which is the

56:05

dihydroxyacetone phosphate. So where is that?

56:08

So when you look at glycolysis,

56:11

it starts off with glucose which is 6

56:13

carbon, then goes to glucose 6 phosphate which

56:15

is 6 carbon, then fructose 6 phosphate which

56:17

is 6 carbon, then fructose 1 6 bisphosphate

56:19

which is 6 carbon, but then it splits

56:21

off into 2, 3 carbon molecules.

56:24

So one is glyceraldehyde 3

56:26

phosphate and the other is

56:28

dihydroxyacetone phosphate, DHAP. They're

56:31

interchangeable. Predominantly the DHAP

56:33

will turn into glyceraldehyde 3 phosphate and create

56:35

2 molecules of that all the way down

56:38

until it creates 2 molecules of pyruvate. From

56:40

1 glucose. That's right. But here,

56:43

trying to reverse that, glyceral

56:46

will jump in at

56:48

DHAP, dihydroxyacetone phosphate and

56:50

then that can reverse all the way

56:52

through to fructose 1 6 bisphosphate, up

56:55

to glucose. So glyceral can be made

56:57

into glucose. So that's gluconeogenic. And again,

56:59

liver. And again, this is

57:01

happening in the liver, primarily in the liver.

57:04

Now if we think about... So if you had those 3 molecules,

57:08

lactate which has come from muscle

57:10

and red blood cell, amino acids

57:12

which are coming technically from any

57:14

tissue, predominantly muscle proteins and then

57:17

you have glycerol which is coming from fat. Yeah.

57:20

Out of those 3, which one would be,

57:22

do you think most effective,

57:25

most utilized in gluconegene? Yeah.

57:28

So if you're looking at an 8 hour fast, right? So

57:31

you wake up in the morning, haven't eaten anything. Like

57:34

I said earlier, 40 to 70% of the glucose

57:36

that's been made is coming from glycogen. The

57:39

next is around is lactate

57:42

and that's constituting around 7 to 18% of

57:44

the glucose that's coming from

57:47

lactate. The next is going to be the

57:50

glycerol and that's going to

57:52

be around about 5 to 8-ish percent. And

57:54

then the next is going to be amino acids which is going to be under

57:57

5%. Right. So

57:59

that's after... eight hours. Again

58:02

an important point here is that

58:04

if you have a think about what's

58:08

happening over time as

58:12

we as we get to

58:14

let's say 12 hours 54%

58:16

of the glucose is coming from

58:18

those gluconeogenic substrates the rest is

58:20

coming from glycogen then

58:23

at 22 hours of fasting. Okay so

58:25

Aaron there now for a whole day. Yes

58:27

so now 22 hours of fasting whole day

58:30

basically 64% of

58:32

the glucose is making is coming from those gluconeogenic

58:35

substrates. Okay so from lactate. But 42 hours. Okay

58:37

so now two days he's there.

58:43

Yeah 84% of his

58:45

glucose is coming from gluconeogenic substrates.

58:47

Okay so he's completely exhausted his

58:49

glycogen. Pretty much. None left. Yeah

58:51

and now he's relying on lactate,

58:54

glycerol, and amino

58:56

acids. Yes. Now will you just keep

58:58

because I always always understanding

59:00

my main I mentioned this last

59:02

podcast but I was always under

59:05

the impression that you

59:07

don't really want to keep breaking your muscles down. So

59:10

is there a point where amino acids kind of go

59:15

breaking the muscles down for energy? No. No

59:17

it's just gonna keep going. But remember it's

59:19

only contributing like 5% of

59:22

the glucose. Not a huge amount. No I mean

59:24

it increases as the glycogen goes down but overall

59:27

it's the least. Because I would

59:29

imagine lactate fairly steady it's

59:31

constant because red blood cells is always

59:33

going to produce lactate regardless. That's it's

59:35

an end point. In the liver alanine

59:38

contributes 6 to 11 percent so it's higher

59:41

than the average amino acid. That's as good

59:43

as more of it. Yeah it's actually a

59:45

little bit higher than in

59:48

the liver. So which can be up to

59:50

7 odd percent. Now for

59:53

the liver to be producing glucose which

59:55

we said is predominantly for the lens,

59:57

the red blood cells, the brain. Yeah.

1:00:01

There is still... Well, this process of

1:00:03

making eukaryotic glucose requires a lot of

1:00:05

energy, right? It does, yeah,

1:00:07

which is strange because you'd think, I've got

1:00:10

no energy. How am I getting this energy?

1:00:12

So how does the liver... How

1:00:15

is it able to keep driving

1:00:17

this gluconeogenesis process? Great question. Remember

1:00:19

we said we're breaking down triglycerides

1:00:22

to release the glycerol? Yeah. It

1:00:24

also releases fatty acids. And

1:00:27

those fatty acids can undergo a

1:00:29

process called beta-oxidation where you turn

1:00:31

at least even-chain fatty acids into

1:00:34

acetyl-CoA. So just explain to me

1:00:36

quickly what a fatty acid is. So

1:00:38

a fatty acid is a long

1:00:41

carbon molecule with hydrogens and oxygens attached

1:00:43

to them. Okay. And

1:00:45

so the point of shuffling

1:00:48

this into the mitochondria is

1:00:50

to keep driving the electron

1:00:52

transport chain, really. Well, it's

1:00:54

ultimately to produce acetyl-CoA. Okay.

1:00:56

So this is where it'll come in? This

1:00:58

is where it comes in. In the process

1:01:01

of turning fatty acids to acetyl-CoA, the

1:01:03

process of beta-oxidation, which is

1:01:06

that process, produces NADH and

1:01:09

FADH2. So they're electron

1:01:11

carriers? Yeah. Right now, think

1:01:13

of them as ATP equivalents,

1:01:16

right? Because ultimately, they help produce

1:01:18

ATP. Effectively, they're

1:01:20

probably equivalent to four-ish ATP

1:01:22

molecules. So the argument is

1:01:25

that taking fatty acids and

1:01:27

just turning them into acetyl-CoA

1:01:29

creates ATP. And that ATP

1:01:31

is leveraged by gluconeogenesis to

1:01:34

get it going, to keep it

1:01:36

going. But think about this,

1:01:38

Matt. We're

1:01:40

kicking through this gluconeogenesis, right? Insulin's crazy low

1:01:42

because we've got no glucose. We're trying to

1:01:45

replenish it. So insulin's low. Here's a question

1:01:47

for you. Well, can I finish or not?

1:01:49

No, this is part of the why insulin's

1:01:51

low. Okay. So you are maintaining

1:01:54

glucose levels, though, through gluconeogenesis. Yeah, but

1:01:56

we're eating it up straight away. Yes,

1:01:59

but you... You're still going to, if you can

1:02:01

take a person's blood sugar levels, it's still at four,

1:02:03

let's say, right? So

1:02:05

isn't that enough to generate insulin release? Probably

1:02:08

not because most tissues are insulin independent.

1:02:11

No, but we did speak about this, remember, last

1:02:14

week or last podcast. Remember

1:02:16

when we said when insulin is

1:02:19

released from a meal, a

1:02:21

big part of its release isn't

1:02:23

just the presence of it

1:02:25

in the blood. It's also the

1:02:29

paracryinal environment of the food in

1:02:31

the gut. Yeah, as the

1:02:33

glucose molecule moves through the digestive

1:02:36

tract, it stimulates the release of

1:02:38

GLPs and other molecules, potentiate insulin.

1:02:42

But your argument still stands that if

1:02:44

your blood glucose levels go up, it's

1:02:46

going to stimulate insulin release. But the thing

1:02:48

is... Because remember we did speak about that

1:02:50

if you just injected the person with glucose

1:02:53

and IV, they're not getting the same insulin

1:02:55

response. No, but they are getting an insulin

1:02:57

response. They still, yes. So your point

1:02:59

still stands that if you're mobilizing this glucose into

1:03:01

the blood sugar, you are going to get some

1:03:03

degree of insulin release. But

1:03:06

we're talking upwards of 24 hours now, right?

1:03:09

We're talking well upwards of

1:03:11

24 hours where the

1:03:14

exhausting our glycogen stores. So

1:03:16

the insulin is going to be continually

1:03:18

dropping because we're never going to meet

1:03:21

the demands that we require. I think

1:03:23

the big thing here is the glucagon

1:03:25

to insulin ratio, it's just... What

1:03:28

is it? Low to high. So you've got

1:03:30

a very low ratio of insulin to glucagon.

1:03:32

And that's just outlined any kind of effect

1:03:34

that insulin would have. Insulin is high, insulin

1:03:36

is low. But think about it like

1:03:38

this. When

1:03:41

we've got... So I'm talking about 30

1:03:43

plus hours fasting. We're

1:03:46

trying to make new glucose through

1:03:48

the whole gluconeogenic process. Another big

1:03:50

part of this process is taking

1:03:53

pyruvate, turning it

1:03:55

to oxaloacetate and then pulling

1:03:57

oxaloacetate out of the Krebs cycle. I

1:04:00

said you need oxaloacetate to bind to

1:04:02

acetyl CoA to undergo

1:04:05

the Krebs cycle. So

1:04:08

we're taking triglycerides, splitting

1:04:11

it apart to form glycerol,

1:04:14

which is being fed to make glucose, but

1:04:16

fatty acids, which are turning into acetyl CoA.

1:04:19

So simultaneously, you're producing

1:04:22

huge amounts of acetyl CoA, but

1:04:25

low amounts of oxaloacetate because

1:04:28

you're pulling it out and making glucose from

1:04:30

it. So acetyl CoA has

1:04:32

nothing to bind to for the Krebs cycle

1:04:35

to undergo. So acetyl CoA just accumulates, accumulates,

1:04:37

accumulates. When you

1:04:39

accumulate acetyl CoA, it triggers a

1:04:41

process called ketosis or ketogenesis in

1:04:43

which acetyl CoA molecules sort of

1:04:46

snap together and get slightly modified

1:04:48

to produce ketone bodies. The

1:04:51

main one being beta hydroxybutyrate. There's

1:04:53

others like acetoacetate and so forth. Acetone.

1:04:56

But beta hydroxybutyrate is the main one. So

1:04:59

now what's happened in the liver after

1:05:02

many... Now, don't get me wrong. This

1:05:04

will happen after an eight

1:05:07

hour fast, but it's so low. But as you

1:05:09

get longer and longer and longer... So you're talking

1:05:11

days, really? Yes. This

1:05:14

really starts to accumulate. And so you start

1:05:16

to produce ketones. The ketones

1:05:18

leave the liver and

1:05:20

jump into the bloodstream and go to the brain. And

1:05:23

the brain goes... So it can cross the

1:05:26

blood brain barrier? Yes. And the

1:05:28

brain's got no glucose at the moment because it's going, where the hell

1:05:30

is all this glucose? You're not eating anything.

1:05:32

Oh, it's minimal. It's very minimal. The ketones

1:05:34

jump into the brain and just turn

1:05:36

back into acetyl CoA. And

1:05:38

listener might think, yeah, but that was the problem in the

1:05:40

first place. You

1:05:43

can have acetyl CoA, but if there's no oxaloacetate,

1:05:45

how do they bind together to undergo

1:05:48

the Krebs cycle? Remember that gluconeogenesis, the

1:05:50

process of taking that oxaloacetate out of

1:05:52

the Krebs cycle to make glucose, is

1:05:54

only happening in the liver. The

1:05:57

brain has a normal amount of oxaloacetate.

1:06:00

relatively normal amounts of oxaloacetate. So

1:06:02

ketones can be used to turn

1:06:04

into acetyl-CoA to bind to oxaloacetate

1:06:06

for the Krebs cycle to occur

1:06:08

and the brain gets ATP. Right.

1:06:11

And so that's why ketones are

1:06:13

used as a backup

1:06:16

energy source, not primary energy

1:06:18

source, dear carnivore, but

1:06:20

a backup energy source once

1:06:24

glucose is exhausted and insulin

1:06:27

is very low, that's an

1:06:30

important point because diabetes,

1:06:34

if people aren't managing their diabetes very well and

1:06:36

their insulin is basically absent, they

1:06:39

start to mobilize fat. So this would be... Just

1:06:41

like they're starving. So this would be more likely

1:06:43

in states of type 1 diabetes.

1:06:46

It can happen in 2, but

1:06:48

it's less common. That's one, yeah.

1:06:50

Because one, you are completely absent

1:06:53

of insulin. Yes. And

1:06:55

usually in these cases, the person is

1:06:57

in a stress situation. That's right. Like

1:07:00

they've just had a serious infection,

1:07:02

they've just had surgery, maybe

1:07:05

they've had a bender like a lot

1:07:07

of alcohol that could go with hypoglycemia

1:07:10

or exercising

1:07:13

vigorously. Yeah. So they're kind

1:07:15

of mimicking what we're just talking about now. Yes. But

1:07:18

they are now going into a huge

1:07:20

amount of fatty acid mobilization and the

1:07:23

liver's been bombarded with

1:07:26

beta oxidation. Yeah. Therefore,

1:07:28

acetylcholine is in abundance and

1:07:30

now they're producing a huge amount of

1:07:32

ketones. Now the problems with ketones is

1:07:35

they're acid forming. Yeah. And

1:07:37

so then you're likely to go into an

1:07:39

acidotic state and that in conjunction

1:07:43

with the low sugars,

1:07:45

it's going

1:07:48

to cause the problem. Well, actually, it's actually high

1:07:50

sugars and you just can't utilize them. Exactly.

1:07:53

But they're basically not there. Yeah. Even

1:07:56

though the brain can use them, but

1:07:58

the problem is the fact that they're not there. that when

1:08:00

you make ketones you make acid. Yep.

1:08:02

And that can lead to... But with

1:08:05

hypoglycemia, I'm going to confuse everyone now

1:08:07

because we're talking about hypoglycemia. But because

1:08:09

you're on hypoglycemic you're going to produce

1:08:11

over a threshold in your kidneys, you're

1:08:14

going to lose a lot of water,

1:08:16

you're going to have electrolyte imbalances and

1:08:18

so you're going to have hypotension in

1:08:21

conjunction with the high

1:08:24

acid, that's going to

1:08:26

be buffered by potassium, so you're going to have

1:08:28

potassium issues, so this is whole cascaded effects which

1:08:30

is going to cause the problem with a DKA.

1:08:32

Yes. So

1:08:35

at the end of all this what we find

1:08:38

is that... So in

1:08:40

his case five days, he lost

1:08:42

30 pounds. Unsurprising. And so

1:08:44

that would have been predominantly all fat.

1:08:46

And some water. I

1:08:48

don't know. Yeah, he definitely had very

1:08:51

limited amounts. But he would have been burning

1:08:53

through his fat stores. Yes, absolutely.

1:08:56

Absolutely. Just to try and generate that glucose.

1:08:58

Glucose is important. You're never going to get

1:09:00

sick of glucose. If you're cutting all the

1:09:02

sugar out of your diet, you're

1:09:05

inevitably going to go back to sugar because your brain

1:09:07

wants it. Your red blood cells want it. They

1:09:09

need it effectively. And if they don't get it from the

1:09:11

diet, they'll make it from the fat. And that's obviously one

1:09:14

way that people can get it. So what are red blood

1:09:16

cells? Because they don't have a

1:09:18

mitochondria to use ketones. So

1:09:20

are they still entirely

1:09:23

reliant on glucose? Yeah. So it

1:09:26

just has to remain there. I

1:09:28

think there is a backup energy

1:09:30

source that can use it. I can't remember what

1:09:32

it is, but it is basically glucose. Very

1:09:35

important. Anything else you

1:09:37

want to add to this? We've

1:09:40

pretty much covered most of... I was

1:09:42

just going to mention some of the glycogen

1:09:44

storing. Oh, yeah, yeah, yeah, yeah, yeah. So

1:09:46

these are just some autosomal

1:09:50

recessive disorders that

1:09:52

when you look at the way the

1:09:54

glycogen is stored and then

1:09:57

broken down, that there

1:09:59

are... enzymes that have gone

1:10:01

awry in these types

1:10:06

of glycogen storage diseases.

1:10:09

But there's only a handful that are relatively

1:10:12

common. So I

1:10:14

was just going to mention when you spoke about the

1:10:16

way that glycogen is stored in the liver. So

1:10:20

it's kind of like you're

1:10:23

just putting glucose molecules on

1:10:25

top of each other and trying to just compact it into

1:10:27

a small space. Like Lego blocks

1:10:29

right? Lego blocks but in

1:10:31

branches. So it's kind

1:10:33

of like you go to a certain

1:10:36

number of glucose molecules in a row, which is

1:10:38

a stem, and then all of a sudden you

1:10:40

make a new branch. You let that

1:10:42

run for a period and then on the branch. And

1:10:45

this just makes a very bushy bush. Oh,

1:10:48

okay. Bushy bush. So

1:10:50

with the glycogen storage

1:10:54

disorders, there

1:10:56

are, as I said, about 15 of

1:10:58

them subtypes. And

1:11:01

the most common are type 1,

1:11:03

2, 3 and 5. Okay.

1:11:06

What I can do quickly is I'll

1:11:08

just say this is what's happened with

1:11:11

the enzyme that's not working. And

1:11:13

you maybe suppose what

1:11:16

you would expect to happen. Sure. So the first

1:11:18

one is in terms

1:11:22

of the type. It's

1:11:24

a type 1 storage

1:11:27

disorder and the deficiencies in

1:11:29

the glucose 6 phosphatase. Okay.

1:11:32

So this is the enzyme that

1:11:34

is changing. It's like

1:11:36

the final step of gluconeogenesis. 6,

1:11:39

glucose phosphate into glucose. Yeah. So

1:11:42

what would you expect to happen if that

1:11:44

one stopped working? Everything backs up. Glycogen backs

1:11:46

up. Everything that's trying to

1:11:48

feed backwards. There'd be no gluconeogenesis because

1:11:50

it can't feed to its final step.

1:11:53

So it's sort of like you

1:11:56

have all these different, it's

1:11:58

like everyone from Victoria, New South Wales. and

1:12:00

South Australia come to Queensland. They

1:12:06

can all get to the border but they just can't get in.

1:12:09

So everything will just back up into

1:12:11

their own states. And so while their

1:12:13

roads aren't blocked, the very last point is

1:12:15

blocked. And so my thought would be that

1:12:17

everything will just feed into glycogen. Everything

1:12:21

will just feed into just continually

1:12:23

storing glycogen but

1:12:26

not being able to use glycogen for glucose production. So

1:12:29

this is a fasting state. You can't

1:12:31

access glucose. So this is

1:12:33

the problem. It's only in a fasting state. So if

1:12:35

the person is in a fed state, usually

1:12:38

a child, they're not going to

1:12:40

experience any symptoms. Of course, because it's going

1:12:42

in the opposite direction. So

1:12:44

it's only going to be a problem when you're

1:12:46

trying to liberate in the early fast. So they

1:12:49

have to constantly be in the fed state? I

1:12:51

guess so. So they've got to be... If

1:12:54

they're trying to break down glycogen, they

1:12:56

can't break it down anymore and they

1:12:58

can't produce new glucose from glycogenogenesis because

1:13:00

that final step doesn't work. Sounds right.

1:13:02

Good. Sounds good when

1:13:04

I'm right. But some of the

1:13:06

other side points of it not working would

1:13:08

be, well, they're

1:13:10

not going to be... What's

1:13:13

one of the inputs of glycogenesis?

1:13:17

Amino acids, glycerol,

1:13:19

lactate. Lactate, right. So

1:13:21

the lactate levels in their blood go

1:13:23

up. Oh, yeah, because it backs up as lactate.

1:13:25

Right. Because they've got no way of clearing it. Oh,

1:13:28

okay. That's a lot of great. So that

1:13:30

goes up. Now, also because you're running out

1:13:32

of glucose, you're trying to get it

1:13:35

from other sources. So fat... Well,

1:13:38

so you get a lot of lipolysis. That's

1:13:40

right. But also your cholesterol levels in

1:13:43

blood. That was very high. It backs up

1:13:45

into the system. And the other one is, because

1:13:47

you're trying to... During the fast, you're

1:13:50

trying to generate ATP still. Yeah.

1:13:54

You're trying to get those electron carriers, but because you're

1:13:56

not being able to do it through other means, you

1:13:58

are shooting off other pathways. and one is

1:14:00

the pentose pathway, which is one method

1:14:03

of the side of glycolysis to generate

1:14:06

those electron carriers. One

1:14:08

of the side points of, or the end points

1:14:10

of the pentose pathway is uric acid. And

1:14:13

so they can generate or they develop a

1:14:15

condition called gout. Yep. Okay. What's

1:14:19

another one? The next one is type two. This

1:14:21

is Pompeisa disease. Now when you look at glycogen

1:14:24

in the muscle, that is broken

1:14:26

down in a lysosome. Okay.

1:14:30

So that whole process of glycogen

1:14:35

breakdown, all the

1:14:37

enzymes that we spoke about actually happens in

1:14:39

a lysosome. In a muscle. Yeah. Now

1:14:42

the enzyme lysosome acid maltase. Acid

1:14:46

maltase. Lysosome or

1:14:48

acid maltase. Okay. That's

1:14:50

an enzyme that plays an important role in the glycogen

1:14:53

breakdown. That is the mutation in this

1:14:55

particular case. And so the

1:14:57

lysosome doesn't have its ability to break

1:14:59

down glycogen effectively. And glycogen

1:15:01

starts to accumulate in muscle. This is only

1:15:03

a muscle because our

1:15:06

liver doesn't do it in a lysosome. Oh,

1:15:08

okay. And so muscles will start to accumulate.

1:15:10

So the lysosome will disorder then, would you

1:15:12

call it? It's

1:15:14

still an enzyme, but it's in the lysosome.

1:15:17

So you've got glycogen so they get muscle weakness? Well,

1:15:20

they'll just get accumulation of

1:15:22

the glycogen products in the muscle. So

1:15:25

they get big hypertrophy. Yes. And

1:15:27

that would be in all types of muscle. Interesting. So

1:15:30

it would be in smooth. Yeah. It

1:15:32

would be in heart. So they get cardiac myopetes. Wow.

1:15:34

They get it in skeletal muscles. And they

1:15:37

probably end up dying from respiratory

1:15:39

failure. Why? Well.

1:15:42

Sclerobuscles and diaphragm. Yeah. And

1:15:44

then they have feeding disorders because the

1:15:47

gastroenteric contract smooth muscle. So

1:15:49

that can't. All right. Yeah. Next

1:15:52

one. Do you want to go through them all? Two

1:15:55

more? Yeah. Okay. The

1:15:58

next one is. disease

1:16:00

so it's a type 3. Is that

1:16:02

associated with the Cori cycle? You think

1:16:04

so but no maybe it's the same

1:16:06

guy. Is it the lactate cycle? Yeah.

1:16:08

Because we spoke about lactate leaving muscle

1:16:11

entering as pyruvate leaving

1:16:13

as glucose turning

1:16:15

into lactate and going back and forward that's the

1:16:17

Cori cycle. That's the Cori cycle. No but

1:16:20

I'm assuming the same person who named

1:16:23

that C-O-R-I. C-O-R-I. Yeah

1:16:26

that's the same. Okay go on. But it's

1:16:28

not the same cycle. Okay so this in

1:16:30

this particular case the problem is a d-branch

1:16:32

an enzyme so this is where

1:16:34

you're putting to make

1:16:36

glucose you're going glucose glucose

1:16:39

glucose branch and where

1:16:41

you put the branch instead of the

1:16:43

carbon 1 to 4 on the stem you're doing

1:16:45

1 to 6. Okay. To cut that which is

1:16:47

an enzyme you don't have it. So again you're

1:16:51

having the same problem as the

1:16:54

type 1. But basically storing cellulose.

1:16:57

Kind of. Yeah you're not being able to

1:16:59

break it completely so you got chunks of

1:17:01

glycogen when you're trying to break it down.

1:17:03

And same symptomatology. Well the only difference between

1:17:05

the first one the first one was

1:17:08

glycosine phosphatase which is a regulatory

1:17:10

step for gluconeogenesis. This one isn't.

1:17:13

So all your gluconeogenesis is still

1:17:15

working. Right you just can't use

1:17:17

the glycogen. That's right. So you'll

1:17:20

still develop hypoglycemia in an early

1:17:22

fast because remember you spoke about

1:17:24

glycogen being the first primary source but you

1:17:27

can still overcome it through gluconeogenesis. So it's

1:17:29

not as severe. So one of the treatments

1:17:31

for this is just less sugar intake because

1:17:34

you can rely on gluconeogenesis. I think

1:17:36

it's the treatment here but I'm

1:17:38

happy to be correct it is a lot

1:17:40

more complex carbohydrates in your diet. Okay

1:17:44

what's the last one because I want to talk about ethanol

1:17:46

metabolism quickly before we go. The last

1:17:48

one is mccardal. This

1:17:51

is a type 5. Alright. And

1:17:54

this one is a phosphorylase

1:17:57

a glycogen phosphorylase which is This

1:18:01

is a glucagon dependent enzyme

1:18:03

so it needs to be phosphorylated for it

1:18:05

to work. This

1:18:08

is only in the muscle though and so this

1:18:10

would be kind of a less severe form

1:18:12

of the Pompeii disease. Oh okay, cool. But

1:18:15

that one is kind

1:18:18

of like if you can keep the muscle out

1:18:21

of a fasting state

1:18:23

or when it's highly

1:18:26

dependent on glycogen it should be

1:18:28

okay. So my thought would be

1:18:30

constantly feeding but not a lot.

1:18:33

Not extremely exercise where it needs

1:18:35

to be using glycogen. How

1:18:39

common are these metabolic

1:18:41

diseases? They're actually rare right?

1:18:44

Well probably in the paediatric population which

1:18:46

they are prevalent. But they're not even

1:18:48

running lethal right? Yes, you

1:18:51

mean leading to death? Yes, yes. Oh they

1:18:53

are? Some of them are. Some of them

1:18:56

may require enzymatic injections

1:19:00

but I think some are just you can't overcome

1:19:03

that because it's so widespread. But

1:19:05

they are autosomal recessive so you obviously

1:19:07

need two of them from each

1:19:10

parent. Because of the loss of function. Because all

1:19:12

of these have been loss of functions. And

1:19:15

I'm guessing these may be

1:19:17

conditions that we will look to in the future

1:19:19

to have genetic manipulation

1:19:21

to overcome these. Ethanol.

1:19:26

Alcohol. We

1:19:28

can use ethanol to

1:19:30

make energy. So it

1:19:32

isn't gluconeogenic as a substrate

1:19:35

because it doesn't make glucose. But

1:19:37

ethanol makes abundant energy. And

1:19:40

that was the hypothesis I

1:19:42

read some time ago. Animals

1:19:46

that developed the ability to break down ethanol

1:19:48

for energy. Because if you think about it,

1:19:52

let's say primates which

1:19:55

would have been eating fruits. Fruits

1:19:58

is obviously... Yeah, like in ferment. a

1:20:00

fruit is a source of a lot of sugar,

1:20:02

right? But if it started fermenting, you

1:20:05

would lose the benefit of going, well now it's

1:20:07

not gonna be useful for energy metabolism, right? But

1:20:09

if you have the ability to break down the

1:20:12

ethanol, which is, then it is. So

1:20:14

there's a benefit for the primate, let's

1:20:16

just say, to be able to

1:20:18

process ethanol. But here's the detriment. So

1:20:20

when you take ethanol, ethanol's poisonous, right?

1:20:22

Like it's not a great thing for

1:20:25

us. We need to metabolize ethanol. So

1:20:27

we turn ethanol into acetylaldehyde. When

1:20:29

we do that, we create NADH.

1:20:33

And that's where we get the energy from, right?

1:20:35

Because we can feed that to oxidative phosphorylation. And

1:20:37

you might think, oh cool, ethanol, we get energy.

1:20:40

The acetylaldehyde needs to

1:20:42

be further broken down

1:20:44

into acetate, which

1:20:47

is done in the mitochondria. And that creates

1:20:49

even more NADH, more energy, brilliant. The

1:20:51

acetate then needs to go back into the bloodstream

1:20:53

and need to be peed out and gotten rid

1:20:55

of. The

1:20:58

problem is the NADH

1:21:00

that we make, which would think that's

1:21:02

weird. If you

1:21:05

are getting NADH from ethanol,

1:21:08

the NADH levels go pretty high.

1:21:11

And high levels of NADH

1:21:14

is like having high levels of ATP. It's

1:21:17

a negative regulator of

1:21:19

glycolysis in the Krebs cycle. It

1:21:21

says we've got enough energy, which

1:21:23

is a pro-storage signal. So

1:21:25

it then tells the body, if you're drinking alcohol,

1:21:27

then you're eating a lot of glucose. Because you

1:21:30

drink a lot of piss, you get a lot

1:21:32

of alcohol in, you start to get hungry, right?

1:21:34

Is that why you get hungry? One of the

1:21:36

reasons why you get hungry is because you're not

1:21:38

using the glucose for energy. Because

1:21:41

it says we've got enough energy. So

1:21:43

it says, oh, it's pro-storage now. So it

1:21:46

doesn't just turn the glucose into glycogen. It

1:21:48

pushes it into fatty acid synthesis as well,

1:21:51

because we've got heaps of it. And

1:21:53

so you actually start to produce fatty

1:21:56

acids. And you start to

1:21:58

produce triglycerides and VLDLs. and from...

1:22:01

Why you get fatty liver? That's

1:22:04

right. Alcoholic fatty liver disease.

1:22:06

But you also get hypoglycemia

1:22:09

because of that, because the glucose has

1:22:11

been stored. But also because,

1:22:13

and you get reduced gluconeogenesis, but

1:22:15

you also get hypolybodemia as well.

1:22:18

So the ethanol, simply just by

1:22:20

boosting those NADH levels, is

1:22:22

negatively regulating all those things, resulting in

1:22:24

just sort of like tweaking the metabolic

1:22:27

pathways just off kilter a little bit,

1:22:30

so that it's now in a post-storage state.

1:22:32

Do you think that's how it kills bacteria?

1:22:36

No, I think it just puts holes straight into

1:22:38

them, doesn't it? Oh, does it? Yeah, because

1:22:40

ethanol is produced by... That's

1:22:44

a product. That's like yeast, right?

1:22:47

Yeah, that's like us producing carbon

1:22:49

dioxide or lactate. Correct, but in

1:22:51

doing so, it's inhibiting

1:22:55

bacteria. Yeah, well, it's

1:22:57

a byproduct, I suppose. So do you think that

1:22:59

is a method of how it keeps away from

1:23:01

each other? I assume so. I assume

1:23:03

so. But yeah, I thought that was interesting. Have

1:23:08

we covered fasting state, Matt? I think so. Well,

1:23:10

I'd just like to thank the Biochemical Society.

1:23:13

I'd like to thank our dear listener.

1:23:16

I realised on our website that we've

1:23:18

got hundreds of unread

1:23:21

emails there, which were

1:23:23

hidden from us, Matt. Hidden from us, but I've got them

1:23:25

now. So what I thought was

1:23:27

happening is that

1:23:29

we were bypassing our website into

1:23:32

our personal email. Because

1:23:34

I was receiving a lot of

1:23:36

emails from people that was complimenting

1:23:38

or asking questions or

1:23:40

spamming. And I assumed

1:23:43

that we were just getting everything that was coming through the

1:23:45

website. There's heaps. So if you've

1:23:47

sent us an email and we haven't addressed

1:23:49

it or spoken about it or thanked you,

1:23:51

we're going to try and do that very

1:23:53

soon. We may not get through all

1:23:55

of that. We may not get through all of them, but I'm

1:23:57

going to be downloading them. But we

1:23:59

are doing... we are doing episodes where

1:24:01

we are answering questions. Yes, so send

1:24:03

us your email again if

1:24:06

we haven't got back to you or

1:24:08

if we haven't spoken or mentioned your

1:24:10

email on the podcast. Send

1:24:12

us another email because it's probably one of

1:24:14

those ones that Matt didn't

1:24:16

read. But

1:24:19

look you can contact us on social media at

1:24:22

drmiketodorovic or you can send

1:24:24

us an email [email protected]

1:24:30

or you can go to our website and we

1:24:32

will read it and access it now or

1:24:35

you can send us an email admin

1:24:37

at drmatt.com.au Apart

1:24:40

from that look we're

1:24:42

just... I'm gonna go eat. Yeah I'm

1:24:45

not starving but I feel like

1:24:48

I need some food. My blood glucose levels are

1:24:51

starting to fall. Hold

1:25:30

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1:25:32

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1:25:34

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