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head over to peteratea.com forward

1:01

slash subscribe. My

1:04

guest this week is Dr. Ralph

1:06

DeFranzo. Ralph is a distinguished

1:08

diabetes researcher and clinician known for

1:11

his pivotal work in advancing

1:13

the understanding and treatment of type 2

1:15

diabetes. He's widely recognized for his

1:17

groundbreaking contribution. to the concept of

1:19

insulin resistance, which has reshaped the

1:21

understanding of type 2 diabetes and

1:23

its progression. He played a

1:25

very important role in bringing metformin to the

1:27

United States as a standard treatment for

1:29

the disease nearly 40 years ago, along

1:31

with the discovery and development of

1:33

SGLT2 inhibitor, a class of

1:36

drugs you have no doubt heard

1:38

me discuss many times before, with

1:40

over five decades of Research

1:43

in the field, Dr. DeFranzo has

1:45

received numerous prestigious accolades, including

1:47

the Banting and Claude Bernard awards,

1:49

the highest honors that can

1:51

be given to a diabetologist. This

1:54

episode with Ralph is really

1:56

a master class in the

1:58

organ specific aspects, the

2:00

pharmacology, the diagnosis of type 2

2:02

diabetes, and it draws from

2:04

his vast experience. Now, if you

2:06

listened to my conversation with Jerry Shulman a few

2:08

years ago on insulin resistance, what

2:11

amazed me was how little

2:13

overlap there was, not because the information

2:15

is not congruent, but because of how

2:17

much we were able to go into

2:19

different topics. So the discussion with Jerry

2:21

Shulman, which I would encourage everyone to

2:23

listen to if they have not, really

2:26

focused on one of the

2:28

areas that insulin resistance manifests

2:30

itself, which is in the

2:32

muscle. What we talk about here

2:34

is about all of the other organs. Spoiler

2:37

alert, there are seven. that are

2:39

impacted by this condition and

2:41

therefore we go into much

2:43

greater detail there in addition

2:45

to the pharmacologic interventions and

2:47

I just have to say

2:49

I learned more in this

2:51

podcast than I do in most

2:53

podcasts. It's one of the few

2:55

that I had to immediately go back

2:58

and listen to and my notes from

3:00

this podcast are so voluminous

3:02

that they even provided substrate

3:04

for internal meetings. with our

3:06

team in the practice. In

3:08

short, there are many things that I've taken

3:10

away from this that will directly impact my

3:13

patients. Just as far as some

3:15

of the other things we discuss, we

3:17

get into details about how insulin

3:19

resistance impacts liver. We do

3:21

talk about muscle, but we talk more about

3:23

fat cells. We talk about his development of

3:25

the euglycemic clamp, something that some of you

3:27

have probably heard of as the gold standard

3:29

for measuring insulin resistance. Again, we

3:31

talk about the pharmacology, not just the

3:34

SELT2 inhibitors, but the GLP1. agonists,

3:36

metformin, and another class of drug

3:38

that we don't talk about that often

3:41

that, frankly, for me was a

3:43

real eye -opener. There's a lot more I

3:45

can say, but I think at the end the day,

3:47

you just kind of got to listen to this one

3:49

maybe twice. So without further delay, please enjoy my conversation

3:51

with Dr. Ralph DeFranzo. Ralph,

3:57

thank you so much for coming

3:59

down to, I guess, up to Austin from

4:01

San Antonio. Very excited to sit down

4:03

with you and talk about potentially

4:06

one of the most important subject matters

4:08

in all of health. People who listen

4:10

to me all the time here and

4:12

are familiar with me talking about these

4:14

four horsemen, cardiovascular disease and cerebral vascular

4:16

disease, cancer, neurodegenerative and dementing diseases.

4:18

And then there's this fourth horseman that

4:20

I talk about and it's in many

4:22

ways the squishiest because it's not the

4:24

one that shows up on the most

4:26

death certificates, but in many

4:28

ways it's the foundational one that

4:30

is amplifying the risk of all

4:33

of those other causes of death.

4:35

And I refer to it as

4:37

metabolic disease spanning the spectrum from

4:39

hyperinsulinemia to insulin resistance to fatty

4:41

liver disease all the way out

4:43

to type 2 diabetes. So

4:46

given how much I speak

4:48

about that, it seems very important

4:50

that we should have a

4:52

really thorough discussion of that foundational

4:54

metabolic disease and no one

4:56

better than you to have that

4:58

discussion. So, let's start a

5:00

little bit with just telling folks

5:02

briefly about what you're doing at UT

5:04

San Antonio and why you've spent

5:06

the last 40 plus almost 50 years

5:09

now working on this problem. Yeah,

5:11

more than 50 years. I actually have

5:13

been in this field of metabolic

5:15

disease for a long time. I think

5:17

I'm the longest consecutively funded 53

5:19

years NIDDDK investigator. I

5:21

actually started even long before that. When

5:24

I was a medical student at Harvard, I

5:26

had this fantastic teacher, Professor

5:28

Cahill, who gave us all

5:30

of the lectures on intermediary metabolism.

5:33

And I decided, this is what I wanted to

5:36

do. And I worked each

5:38

summer with Professor Cahill. And sometimes in

5:40

life, you meet the right person,

5:42

the right opportunity. It changes everything

5:44

you do. And basically what I

5:46

do now, I contribute directly to

5:48

George. And when I gave

5:50

the Banting lecture in 2008, people

5:52

usually put a picture of their mother and

5:55

father and children and I love my

5:57

mother and father and children but I only

5:59

showed one picture and that was Professor

6:01

Cahill because he's really the person

6:03

who's ended up directing me to

6:05

where I am today. People who

6:07

are listening who are particularly astute

6:09

might recall I've referenced the number

6:11

of Cahill's papers but one of

6:13

the more interesting studies he did which it's

6:15

possible he did while you were even a

6:17

student there was the 40 -day starvation study. Now,

6:20

you might have not been quite at

6:22

Harvard yet, because this was, if I

6:24

recall, in the mid -60s, maybe 66, 67.

6:27

And it was probably a group of medical students

6:29

that actually volunteered, if not medical students, undergrads.

6:31

They did a water only fast for 40

6:34

days. And the study basically

6:36

just followed all of the metabolites.

6:38

What happened to glucose levels, obviously

6:40

insulin, beta hydroxybutyretacy, to acetate. Anyway,

6:42

it was very fascinating stuff. One

6:44

of the things that was most

6:46

interesting to me in that study

6:48

was even under a period

6:50

of such extreme starvation, the

6:52

brain never gave up its dependency on

6:54

glucose. So even though

6:56

ketone bodies began to service the brain

6:58

by about day seven to ten

7:00

as the majority of the fuel,

7:03

even at three and four weeks

7:05

of starvation, glucose was, if my

7:07

memory serves me correctly, still providing

7:09

about a third of the brain's

7:11

energy. Your memory is very good.

7:13

The brain did switch over to ketone

7:15

metabolism, and believe it or not, I

7:17

didn't do the 40 -day fast, but

7:19

I was one of the people

7:22

who fasted for five to seven

7:24

days. If you fasted for three

7:26

days, you could get paid $50.

7:29

And I thought I was the richest

7:31

guy in the world from this study.

7:33

I can assure you that the physical

7:35

specimens in this study were phenomenal. What

7:37

did the 40 -day fasting students get? I

7:39

don't know, but I'm sure he paid them

7:42

a lot of money in order to do

7:44

that. The interesting thing about that is you

7:46

realize that We have so much

7:48

energy stored in the human body. Who would

7:50

have thought that you're a lean type

7:52

person? You can fast for 40 days, but

7:54

the real problem is at some point, cardiac

8:00

muscle then prolong fasting at

8:02

that point. becomes a problem.

8:04

But you have a lot of energy stored

8:06

in fat and you can starve for a

8:08

long time. obese people easily can go for

8:10

three, four months with all the reserves that

8:12

are in the body. maybe

8:15

Talk a little bit about what

8:17

insulin resistance is. We'll get into

8:19

what causes it, but let's just

8:21

maybe define for people this term

8:23

that gets thrown around constantly. And

8:25

let's explain what it is from a technical

8:27

standpoint. Basically, every time you

8:30

eat a meal and your blood sugar level goes

8:32

up, you're going to release insulin. And

8:34

insulin is sort of a master regulator

8:36

for all biochemical processes in the body.

8:38

One of the things that insulin is

8:40

going to do is going to talk

8:42

to your muscles and say, take up

8:44

glucose and burn that glucose. What

8:47

we need to know is, in a normal

8:49

person, when I infuse insulin, how

8:51

much of the glucose is taken up by

8:53

the muscle. And then we could

8:55

look at someone who is, say, overweight,

8:57

or we could look at someone who's diabetic, and

8:59

I actually developed the gold standard technique,

9:01

which is the insulin clamp technique, to

9:03

look at this. So we could take an

9:06

obese person or a diabetic or a normal

9:08

person, we raise the insulin, And

9:10

then I'm using muscle as an example.

9:12

How much glucose is taken up disposed

9:14

of by the muscle. And then

9:16

I can compare if you're overweight

9:18

compared to the lean person. Obese

9:21

people are very insulin resistant in terms of

9:23

muscle glucose uptake. I could look

9:25

at the diabetic. They're even more

9:27

insulin resistant. But there are many

9:29

processes that insulin control. So

9:31

insulin regulates how much fat

9:34

is released from your fat cells.

9:36

And obese people, unfortunately insulin

9:38

keeps the fat in

9:40

your fat cell. But in

9:43

obese people, insulin doesn't work so well.

9:45

So instead of keeping the fat in the

9:47

fat cell, even though your insulin is

9:49

high, you're breaking down the fat. So

9:51

you have to look at each

9:53

individual process that insulin is

9:55

controlling. And so for that process,

9:58

we know this is what a normal person

10:00

should respond like. This is what

10:02

a diabetic responds like. And

10:04

the diabetic is much, much more

10:06

insulin resistant. They're not responding. In

10:09

a certain way, it's a

10:11

general term because insulin controls

10:13

so many things. Protein metabolism.

10:16

Insulin is very important in helping

10:18

you to build protein. So I

10:20

could infuse insulin and we've done

10:22

this using carbon -labeled leucine and we

10:24

can define how insulin promotes protein

10:26

metabolism in a normal healthy person.

10:28

And then I could do the

10:30

same kind of study in an

10:32

obese person. And we know that

10:34

the obese people don't respond to

10:36

the insulin as well in terms

10:38

of aggregating protein metabolism. So

10:41

it's kind of a general term. Does

10:43

that translate not just to

10:45

structural proteins such as enzymes or

10:47

cellular structural proteins, but also

10:49

macro structural proteins such as muscle?

10:51

Absolutely. So I can

10:54

look at specific enzymes within the

10:56

cell. I can look at certain

10:58

genes within the cell that are turned on

11:00

or off, or I can look at

11:02

muscle in terms of muscle as a

11:04

bulk. So there are many ways in

11:06

which you could define insulin resistance, but

11:08

basically whatever the particular process

11:10

you're looking at, you're comparing

11:12

what would be the normal response

11:14

and a normal healthy person compared to

11:16

what might happen in a diabetic

11:18

person or an obese individual. So

11:21

one of the challenges with the term

11:23

insulin resistance is, as you said,

11:25

it's a vague term and it's non

11:28

-specific because the actions of insulin are so

11:30

many. It has an action in the liver,

11:32

it has an action in the muscles, it

11:34

has an action with response to glucose, it

11:36

has an action with response to amino acids,

11:38

and it has an action with response to

11:40

fat, both in the liberation

11:42

of fat, lipolysis, and presumably

11:45

in response to oxidation. Absolutely.

11:47

We'll go through all of these.

11:49

But let's maybe start with

11:51

how the euglycemic clamp test

11:53

is done. Let's assume that

11:56

I'm a healthy enough individual that we

11:58

can use me as a proxy. I

12:00

come into your clinic. What are

12:02

we going to do? How do you run this test? Let

12:04

me bring you back in time when I

12:07

was a fellow because at that time we

12:09

didn't really have a good measure of insulin

12:11

sensitivity. So what people

12:13

would do is you do an oral

12:15

glucose tolerance test and the insulin level would

12:17

go up. Some people would say, I'll

12:19

look at how much insulin comes out compared

12:21

to the rise in glucose. And that's

12:23

a measure of beta cell function. And then

12:25

someone would just turn it around and say, look,

12:28

I'm going to see how much the rise in

12:30

glucose was per insulin. And that's a

12:32

measure of insulin resistance. And it

12:34

was very clear to me, well, this is insane. You

12:37

can't take two variables and then

12:39

just depending upon how you want to

12:41

look at them, switch denominator and numerator.

12:43

So I said, we need to develop

12:45

something that is really More

12:47

specific just to be clear

12:49

Ralph. I mean unfortunately we

12:51

as clinicians are not able

12:53

to do you glycemic clamps

12:56

correct We are still looking

12:58

at oral glycemic tolerance tests

13:00

We are still giving people

13:02

oral glucose and sampling glucose

13:04

and insulin every 30 minutes

13:06

and trying to impute What we

13:08

can which I'd love to come back and

13:10

talk about interpretation but carry on with the

13:12

limitation We actually have done a lot of work

13:14

and how you interpret that so what we say

13:16

it is Why don't we develop a serious

13:18

way? And so we developed a

13:21

technique where I could take 100 people

13:23

and I would infuse insulin initially as

13:25

a priming dose and then just clamp

13:27

the insulin level. So I give a

13:29

prime continuous insulin infusion. I can take

13:31

100 people and all 100 people, I

13:33

can raise your insulin level by 100

13:35

micro units per ml. And I

13:37

can do that for two hours. And now

13:39

I know that the stimulus, the

13:42

insulin stimulus, whether you're lean,

13:44

whether you're obese or whether you're

13:46

diabetic, whatever particular process that

13:48

I want to look at. So

13:50

maybe I wanted to look at how insulin

13:52

shut down a pad of glucose production. And

13:54

actually, we were the first people

13:56

to ever use radioisotopes to trace

13:59

this and show that in normal people,

14:01

insulin shut down glucose production

14:03

by delivery very quickly. But

14:05

obese people and diabetics were very, very

14:07

resistant to the insulin. And then

14:09

we said we wanted to know,

14:11

look, everybody now has got the same

14:13

insulin level. How effectively does that

14:15

insulin stimulate muscle glucose uptake? And

14:18

again, what we showed, and

14:20

these actually were the very first

14:22

unequivocal demonstration, that diabetic

14:24

people, type two, were insulin

14:26

resistant. Before this, there was a

14:28

lot of controversy. Dr.

14:30

Reven, who's the father of insulin

14:32

resistance, I like to think I'm

14:34

the son of Dr. Reven, he's

14:36

a great idol of mine. He

14:38

really was one of the very

14:40

first people to insinuate that diabetics

14:42

were insulin resistant. With the insulin

14:45

clamp, we showed this very definitively.

14:47

And we also know we use

14:49

the label glycerol and free fatty

14:51

acids, and we could show the

14:53

ability of insulin to shut

14:56

down release of lipid from the

14:58

fat cell was markedly impaired. So

15:00

three of the major organs,

15:03

all of this work originally was

15:05

done by us when I was back

15:07

at Yale. Let's summarize those again. We're

15:09

talking about this in an insulin -sensitive person.

15:11

Right out of the gate, insulin is going

15:14

to shut down hepatic glucose output. Absolutely.

15:16

Which again, all of this kind of

15:18

makes sense if you think through the

15:20

pathway. Our liver is constantly putting glucose

15:22

into circulation because the muscles can't

15:24

put glucose into circulation. So

15:26

something has to feed the brain.

15:29

If insulin is high, it suggests glucose

15:31

is already sufficiently high. So let's

15:33

not create more glucose toxicity. Let's

15:35

shut that. Second thing it's going

15:37

to do is it's going to

15:39

take that excess glucose and put

15:41

it in the place where we have

15:43

the largest capacity to store it, which is

15:45

muscle. So point two is

15:47

we increase muscle uptake of

15:50

glucose. And then point three

15:52

you said was it's going

15:54

to shut down lipolysis. It's going

15:56

to shut down the release

15:58

of triglycerides and or

16:00

free fatty acids from the adipose

16:02

tissue. That's very critical. We also,

16:04

when we did these studies, we would

16:06

put a catheter in the hepatic vein and

16:09

in ephemeral artery and ephemeral vein. So we

16:11

could look at the individual tissues. And

16:13

what we showed is that when you infuse

16:15

insulin, say 80 or 90 % of

16:17

the glucose is going to be taken up in muscle.

16:19

Only 10 % is going to be taken up

16:21

in the adipocyte and stored. How much

16:23

in the liver? Basically none. Under

16:26

euglycemic conditions, and we were the first

16:28

to show this conclusively as well,

16:30

there's no glucose uptake in the

16:32

liver by insulin. Just explain to people

16:34

what a euglycemic condition means. Yeah,

16:37

euglycemic means you're fasting glucose when

16:39

you wake up in the morning is

16:41

80. Now you're euglycemic. That means

16:43

when we do the studies, we keep

16:45

your fasting glucose of 80. We don't

16:47

let the glucose change. All we're going to

16:49

do is raise the insulin. And that means you're

16:51

giving glucose? Of course, because if

16:53

we didn't give glucose, then your blood

16:55

sugar level would drop. And then

16:57

you'd release cortisol, you'd release

16:59

epinephrine. I just want to make sure people

17:02

understand that I was going to... back to that. I

17:04

wanted you to finish that point. So let's make sure we go

17:06

back to the test because it's very counterintuitive. So

17:08

I've got a catheter in each arm. I walk

17:10

in off the street. I've been fasting. My

17:12

blood sugar is 80 or 90, whatever

17:14

milligrams per deciliter it is. You

17:16

are going to have to infuse both

17:19

insulin and glucose into each of my

17:21

arms. And the reason is when you

17:23

said a moment ago, you're going to

17:25

steadily increase my insulin and take it

17:27

to a steady state of a hundred. I

17:30

.U. Per... Like we're in a paramele. That's

17:32

a staggeringly high insulin level. Not so

17:34

high. In your eye, after a meal,

17:37

it would be maybe 60. Obese people

17:39

very commonly get to 100. Sure, sure.

17:41

For a healthy person, would never see

17:43

an insulin level that high. And

17:45

if you were not simultaneously running

17:47

glucose into them, you would

17:49

kill them within minutes. Hopefully

17:51

not. Yeah, but to get to the

17:54

point, they would become so profoundly hypoglycemic that

17:56

they would cease to exist. And it

17:58

should be obvious that if you're very sensitive

18:00

to insulin, I have to infuse

18:02

a lot of glucose. But

18:04

the other beauty of it, as I said, when

18:06

I was a young guy at Yale, there

18:08

was a physician in New York,

18:10

Dr. Al Shuler, He was the first

18:12

one to use tritiated glucose to trace

18:14

metabolic pathways. And I said, this is

18:16

astounding. So I actually went to visit

18:18

Dr. Altschuler and learned how he did

18:20

it. So all of the insulin clamp

18:22

studies that we did, we were the

18:25

first people to use tritiated glucose in

18:27

humans and to show that

18:29

the ability of insulin to shut

18:31

down the release of glucose from

18:33

the liver was markedly impaired.

18:35

Sorry to interrupt, but just to make

18:37

sure that people are following us, the

18:40

reason you wanted to use tritiated glucose

18:42

there was not to quantify the total

18:44

amount of glucose disposal. You could do

18:46

that on mass balance. You wanted to

18:48

determine the ultimate fate of glucose. How

18:50

much became hepatic glycogen, if any?

18:52

Sounds like the answer is none.

18:54

How much became muscle glycogen? Sounds

18:56

like you said about 90%. And

18:59

how much ultimately got converted through

19:01

de novo lipogenesis into adipocyte

19:03

or free fatty acid? Sounds like

19:05

that's about 10 % under the

19:07

euglycemic condition. Is that correct?

19:09

Yeah. In general, that's correct, except

19:11

in the muscle, remember, some

19:13

of the glucose is going to be oxidized. So

19:16

if you look at the glucose once it

19:18

gets into the cell, one third would

19:20

go through the glycolytic pathway and

19:22

be oxidized. Right away. Yes. And the

19:24

other two thirds would be stored

19:26

as glycogen. I mean, presumably you're doing

19:28

this test and a person is sedentary.

19:30

Yes. Is muscle that metabolically active at

19:32

rest? I guess it is. Yes. Yeah.

19:35

So that's really interesting. Does that mean

19:37

you're increasing energy expenditure under these conditions?

19:39

Well, of course, in a certain way you

19:41

are, but it's not like when you

19:44

go out and you exercise and you run

19:46

a mile or two. So I would

19:48

say you are turning on a number of

19:50

cycles, which are, of course, going

19:52

to increase energy expenditure, you're generating

19:54

ATP. So there is a

19:56

certain increase in energy expenditure. But

19:59

if I really want to increase energy expenditure, I'd

20:01

get you to go jog five miles

20:03

or so. His exercise is really the

20:05

thing that really increases energy expenditure. And

20:08

Ralph, just for a sense of

20:10

amount, if you're doing this in,

20:12

say, somebody my size who's insulin

20:14

sensitive, how many actual grams of

20:17

glucose would you be able to

20:19

get into the person within the

20:21

hour whilst keeping insulin clamped? So

20:24

I'm going to do it first in terms

20:26

of rates, the way we express it,

20:28

and then I'll translate that. Under

20:30

basal conditions, you wake up

20:32

in the morning and your liver is producing

20:34

and your tissues are taking up about

20:36

two milligram per kilogram body weight per

20:38

minute. Liver is producing,

20:40

that's hepatic glucose output. That's

20:42

hepatic glucose output. Two

20:44

milligram per kilogram body weight per minute. And

20:46

we were the first to actually show this

20:49

many years ago, and this is humans. Mice

20:51

are very, very different, totally different. And that's why

20:53

extrapolating from mice to humans can be a

20:55

problem. Let's just reflect on that for a

20:57

second. People who listen to this

20:59

podcast are probably sick of me saying this, but

21:01

I'm sorry, I just can't stop saying it.

21:04

The liver never ceases to amaze me. It's

21:06

an incredible organ. It's an unbelievable organ.

21:08

And again, I come back to

21:10

this idea. It's the only major

21:12

organ for which we don't have

21:14

extracorporeal support. If your heart, if

21:16

you went into cardiogenic shock and we

21:18

felt we could reverse it in time,

21:20

We could put an intraortic balloon pump

21:22

in you. We could put an IABP

21:24

in you. We could put a left

21:26

ventricular device in you to stem you

21:28

over until we get you out of

21:30

there. If your kidneys are destroyed, we

21:32

can transiently dialyze you. Even if your

21:34

brain is experiencing swelling, we can, you

21:36

know, put enough steroids in you or

21:39

decompress your skull to give you the

21:41

time to recover and keep you alive

21:43

otherwise. Go through all the major organs.

21:45

If your spleen is dinged, take it out. Even

21:47

if you lost your small bowel, we

21:49

could at least transiently keep you alive

21:51

with TPN or something like that. None

21:54

of this is true with the liver. You know, in the

21:56

old days, they actually used

21:58

to use pig liver perfusion. I

22:00

know. But that was in the old

22:02

days. We don't do that anymore. And

22:04

baboon as well. It had baboons. Yeah.

22:06

So the fact that the liver can

22:08

titrate this amount is remarkable. So two

22:10

milligrams per kilogram per minute. So you

22:12

take an individual who weighs 100

22:14

kilograms, You're putting 200

22:17

milligrams per minute of

22:19

glucose into circulation. Then

22:21

you can multiply that

22:23

by however minutes you

22:26

want to look. So that's a gram

22:28

every five minutes. That's

22:30

12 grams of glucose every

22:32

hour that the liver

22:34

is putting out. But now,

22:36

when I do an insulin clamp, depending

22:38

on how much I raise the insulin

22:40

and over the years, we've done a

22:42

dose response curve and I can come

22:44

back to this because your fat is

22:46

exquisitely sensitive to insulin. If

22:49

I raise the insulin just by 10 micro units

22:51

per ml, the fat

22:53

stops producing free fatty acids

22:55

and glycerol. You inhibit

22:57

lipolysis literally, completely. The liver,

22:59

you need to get the insulin up to

23:01

about 50 micro units per ml to really

23:03

get it shut down. Sorry, and the fat,

23:05

you had to get how high? Ten. A

23:08

rise of ten. Tell me, these people, when they

23:10

come in and healthy, they're at five to

23:12

ten faster? Yeah, they're at five to ten. So

23:14

I'm going to raise them from five to

23:16

ten to maybe fifteen or twenty, and that's going

23:18

to, in large part, shut down lipolysis. In

23:21

fact, all of this sort of work was

23:23

work that we originally did many, many years ago.

23:25

Now, at the level of the liver, you

23:27

really need to get up to about fifty micriners

23:29

per ml. So maybe at ten, I'm going

23:31

to bring you up to fifty. and

23:33

that's in large part gonna shut off

23:35

glucose production by the liver. Now,

23:38

that's critical because you

23:40

wake up in the morning and your liver's

23:42

producing glucose. Now, if you eat

23:44

a meal, glucose is coming in

23:46

from the gastrointestinal tract. You can't have glucose

23:48

coming in from the liver at the same

23:51

time. Otherwise, you get very

23:53

hyperglycemic. So when you eat a meal

23:55

and that insulin comes out, it really needs to

23:57

shut down a pad of glucose production. Now,

23:59

what's replacing the liver is what's coming from

24:01

the meal. but then after you absorbed all

24:04

of the meal, the liver needs to turn back

24:06

on. So understanding how the

24:08

liver is responding to insulin is really

24:10

very important. And then if I want

24:12

to look at what's going on in the muscle, the

24:14

reason why we go to 100

24:16

micronutrients per ml, which is above

24:18

physiologic, but it's still within the

24:20

physiologic range, if you really want

24:23

to stimulate muscle glucose uptake completely

24:25

in a normal healthy person, you'd

24:27

probably have to get the

24:29

plasma insulin to about 200

24:31

micronutrients per ml. At 200, what

24:33

happens? You have now maximized

24:35

muscle glucose uptake in reality. Even in

24:37

an insulin sensitive person. Yes. Just

24:39

to make sure I understand what you're

24:42

saying, you're saying that if you

24:44

took an insulin sensitive individual at 100

24:46

units of insulin

24:48

versus 200, you will actually

24:50

drive more glucose uptake. You

24:52

haven't saturated the Glute 4

24:55

transporter at 100. probably about

24:57

25 % more uptake as you go

24:59

from 100 to 200. Wow. And these

25:01

are all early studies that we

25:03

did. So when we talk about insulin

25:05

resistance, that's why I said you need

25:07

to know which tissue you're talking about

25:10

and which metabolic pathway. And

25:12

if you want to talk about enzymes,

25:14

you need to talk at what specific enzyme

25:16

because insulin resistance needs to

25:18

be related to the

25:20

tissue you're talking about and the process

25:22

within the tissue that you're talking about. So

25:25

insulin resistance is a very important

25:27

concept, but you all have to

25:29

be a little bit more specific

25:31

about what aspect you want to

25:33

address. So you can have insulin

25:35

resistance in the fat cell, you can

25:37

have insulin resistance in the liver, you can

25:39

have insulin resistance in the muscle, and

25:41

then something that's now pretty exciting. You may

25:43

have insulin resistance in the brain, and

25:45

there's suggestions now, and there are many

25:48

insulin receptors in the brain. Jesse

25:50

Roth, very famous diabetes person, maybe

25:52

50 or 60 years ago was the

25:54

first to describe insulin receptors in

25:56

the brain. And this is an area

25:58

that's now starting to unfold. It

26:00

may have some relationship

26:03

to neurodegenerative disease, Alzheimer's disease.

26:05

So people say that Alzheimer's disease

26:08

is diabetes type three. And

26:10

I'm not sure. Brain diabetes. Yes.

26:12

So the insulin resistance is

26:14

a very important concept. Let's

26:16

say we're going to talk about diabetes. even

26:18

though there's an ominous octet that I

26:21

developed that's used everywhere in the

26:23

world for the pathophysiology of type 2

26:25

diabetes, if we really wanted to

26:27

solidify it and say, what are the

26:29

two big concepts? Insulin resistance

26:31

would be here, and the other

26:33

hand would be impaired beta cell

26:35

function. So if you are

26:37

insulin resistant and your beta cells work

26:39

well, they know how to read the

26:41

insulin resistance, they'll make enough insulin

26:44

that you won't become diabetic. The

26:46

hyperinsulinemia can damage you in other ways,

26:48

but you won't become diabetic. But

26:50

what happens is if you're insulin resistant,

26:52

particularly if you have a genetic

26:55

predisposition, if your beta cells have to

26:57

continuously pour out insulin, they

26:59

start to exhaust. And insulin

27:01

resistance is a disaster for someone

27:03

who has a genetic predisposition that's

27:05

going to bring out the diabetes. Insulin

27:07

resistance, in my opinion, is

27:10

intimately related to cardiovascular disease. That

27:12

is why when you see

27:14

a diabetic patient, 10 % of

27:16

them, you walk in, you have diabetes, first

27:18

time I see you, 10%, 15 %

27:20

of the people already have

27:22

clinically significant cardiovascular disease. And

27:24

if you look carefully, virtually 100

27:26

% of them do. And sorry, Ralph,

27:28

do you think that that is

27:31

a result of the hyperinsulinemia or the

27:33

untreated or poorly treated hyperglycemia? All

27:35

of the above. More importantly, what we

27:37

showed, and we were, again, the

27:39

first people to show this, and the

27:41

cardiologists, they're hemodynamically

27:44

oriented, they're looking at vessels.

27:47

Stenosis, yeah. But if you look at

27:49

the insulin signaling pathway, insulin

27:51

has got to bind to its receptor. And

27:54

then there's a signaling pathway. I can tell you all

27:56

the molecules in there, which I'm not. And

27:58

then glucose gets transported in the cell.

28:01

We were the first people to show in

28:03

humans that that pathway doesn't work normally. Insulin

28:06

will bind to the receptor. It

28:08

will activate the receptor. But the

28:10

next molecule, IRS1, PI3 kinase,

28:12

All those molecules don't get

28:14

activated, so glucose doesn't get into

28:16

the cell. That's diabetes. That

28:18

same pathway activates

28:20

nitric oxide synthase, and

28:23

that generates nitric oxide. Nitric

28:25

oxide is the most potent

28:27

vasodilator in the human

28:29

body. It's the most potent

28:31

anti -athrogenic molecule in the human

28:33

body. So this defect

28:36

that's in muscle, and it's

28:38

in cardiac muscle, and it's in skeletal

28:40

muscle, This is all human data that I'm

28:42

talking about, not animal data. When

28:44

you get a defect in that insulin signaling

28:46

pathway, that's going to

28:48

cause diabetes and it's going

28:51

to promote cardiovascular disease. And

28:53

that is why you can

28:55

never separate cardiovascular disease from

28:57

diabetes. Now, as you pointed

28:59

out, rightfully so, I

29:02

believe that high levels of

29:04

insulin are also athrogenic. I don't

29:06

want people saying Dr. DeFranco said you

29:08

shouldn't be giving insulin the people

29:10

who need it. Of course, if people

29:12

need insulin, you'd need to give

29:14

them insulin. But our beta cells make

29:16

35 units of insulin per day. So

29:18

we showed this many years ago, and

29:21

actually was at Yale, that

29:23

if you were to take a type

29:25

1 patient and they were lean, they would

29:27

only need 35 or 40 units

29:29

of insulin to get their glucose control,

29:31

assuming you gave the doses at

29:33

the right time. But we have

29:35

a lot of people who are taking a

29:37

hundred units of insulin, both type 1's

29:39

and type 2's. So 3x physiologic. Yes. That

29:41

kind of hyperinsulinemia, I

29:44

think there's evidence to support

29:46

that's atherogenic. But now we have a

29:48

problem. Can you have the glucose remain high? Yeah,

29:50

it's a question of do you want to die

29:52

quickly or slowly? But we have really good drugs.

29:54

Yes, yes, yes. But if you were only doing

29:56

this with insulin. Be a problem. It's an awful

29:58

trade -off. It's you're going to die very quickly

30:00

from hyperglycemia if you're left

30:02

untreated. But if we Overdo

30:04

it with insulin to maintain normal glycemia.

30:06

We're gonna kill you slowly. You're stuck.

30:09

Yeah, you have to treat but

30:11

you also know that when you're giving these

30:13

big doses of insulin there may be some

30:15

side effects. This is something Ralph

30:17

I don't think that has been necessarily

30:19

appreciated by the medical community. Absolutely

30:21

not. There has generally been an

30:23

ethos of when I've talked to

30:26

patients with type 2 diabetes what

30:28

they've been told is I'm told

30:30

to cover with as much

30:32

insulin as is necessary. to

30:34

maintain my glucose levels in

30:36

this range. And it means

30:38

I can eat whatever I want. It's

30:40

okay if I have all the pasta

30:42

and bread and sugar in the world,

30:44

because as long as I'm covering it

30:46

with insulin, I'm okay. And then you

30:48

find out, wow, you're taking 150 units of

30:50

insulin a day in all of its forms,

30:52

the short acting, the long acting, et cetera.

30:55

But I didn't actually realize that what we

30:57

would consider physiologic is 35. I may have

30:59

known that at one point and I've since

31:01

forgotten, but that's a great reference. So

31:03

basically, if there's a person with type

31:05

2 diabetes listening to us today

31:07

and they're taking

31:10

75 units of insulin, one of

31:12

the takeaways should be, what do

31:14

I need to do with my nutrition

31:16

and other pharmacologic activities plus exercise,

31:18

plus everything that's under my control to

31:20

maybe get that down to 35

31:22

where I would be at a physiologic

31:24

level. There are things that in

31:26

already insinuated weight loss if you can

31:28

get people to do it, exercise. And

31:31

then we can add medications

31:33

in combination with insulin, insulin sensitizers,

31:35

or some drugs to help

31:37

you lose weight that will

31:39

also allow you to get

31:41

that dose of insulin reduced. The

31:44

other thing we showed in this

31:46

study, Dr. Del Prado, who's

31:48

past president of the European Diabetes

31:50

Association, we took normal healthy

31:52

lean kids, 18, 25 years

31:55

of age. And we put

31:57

them on the clinical research center

31:59

for three days. And we gave

32:01

them a very, very low dose

32:03

of insulin infusion. And we

32:05

raised their fasting insulin from

32:07

8, which is what a

32:09

normal person would be, to 20, which

32:12

is really quite low. And within

32:14

48 to 72 hours, they

32:16

were as insulin resistant as a

32:18

type 2 diabetic patient. So

32:20

hyperinsulinemia induces insulin resistance.

32:22

Wait a second. Why is

32:25

that the case? What

32:27

insulin does is it down

32:29

-regulates the insulin signaling -transduction system.

32:32

So that insulin, when it binds to

32:34

its receptor, and then it activates IRIS -1

32:36

and PI -3 kinase in AKT, that

32:39

system is down -regulated by hyperinsulinemia. All

32:41

of this that I'm telling you about,

32:43

it's all published, these are all studies

32:45

done in humans, and this

32:47

also been shown in rodent models as

32:49

well. So this is another reason

32:51

why we don't want people to be

32:53

hyper -insulinemic. You have to explain that to

32:56

me again, Ralph. That is mind -boggling. I

32:58

would never have predicted that. So let me

33:00

say it back to you because I feel like I missed

33:02

it when I was writing something down. You took

33:04

normal volunteers who had

33:06

a fasting insulin of eight. And

33:08

they're lean, healthy. Okay. simply

33:12

infused insulin in them, presumably with glucose.

33:14

Oh yes, of course. Yeah. On the

33:16

clinical research center where we can monitor,

33:18

keep the glucose perfectly constant. We're not

33:20

letting the glucose change. A person shows

33:22

up, insulin 8, glucose is 90. You

33:25

do a euglycemic clamp where you bring

33:27

insulin up only by one and a

33:29

half per, one and a half X.

33:31

Much less than would be when you

33:33

eat a meal. Exactly. Not even a

33:35

post -prandial bump, but now it's constitutively sitting

33:37

there at 20. And you've

33:39

obviously had to bring glucose. You had

33:41

to infuse glucose to maintain euglycemia. Correct. Did

33:44

you say that in four days?

33:46

48 to 72 hours. These people

33:48

are as insulin resistant as type

33:50

2 diabetics. Okay. Again,

33:52

very, very counterintuitive. Because

33:55

if our model

33:57

is that insulin

33:59

resistance, which is the

34:01

hallmark factor contributing to type 2 diabetes

34:03

in the combination of beta cell

34:06

fatigue, is driven by Lipotoxicity

34:09

which we're going to come to. It's an important

34:11

one. Yes. These people didn't have any

34:13

of that. These people didn't have

34:15

any of the intramyocellular lipid that

34:17

we talked about with your

34:19

colleague Jerry Reven as a predisposing

34:22

factor. It's the direct

34:24

defect of insulin down regulating

34:26

the insulin signaling system and

34:28

probably other distal metabolic within

34:30

the cell as well. So

34:32

then when you turn the clamps off, let's

34:35

just say we ran this for 72 hours. We've

34:37

made them functionally diabetic. Turn

34:40

the clamps off. How many hours

34:42

days? We didn't do that. What would

34:44

you predict? I would predict probably

34:46

within 24 to 48 hours they would

34:48

return to normal because we did

34:50

this acutely. Now, if we

34:52

were able to do this for several

34:54

months, then I would

34:57

anticipate that the insulin resistance

34:59

would remain for a long period of

35:01

time. And remember, when we

35:03

treat type 1 diabetics, we're always

35:05

giving the insulin into the periphery.

35:07

And you or I, when you

35:09

ingest the meal, where does the

35:11

insulin go? It goes into the portal vein.

35:14

So the liver is seeing a high

35:16

level of insulin. That's good. It

35:18

says stop making glucose, but now it

35:20

removes half of the insulin. So

35:23

how much insulin gets into the

35:25

periphery? Half of what you secreted. Why?

35:28

Because we don't want the insulin

35:30

in the periphery over -insulinizing the

35:32

periphery because it would make the

35:34

muscle tissue very insulin resistant. So

35:36

the pancreas secreting insulin into the

35:38

portal circulation, liver sees the insulin,

35:40

good, stop making glucose, but it

35:42

also takes up half of the

35:44

insulin. So less insulin get

35:46

enough to nourish the muscle, enough

35:48

to shut down the fat

35:50

producing free fatty acids, but not

35:53

enough to hyperinsanize the system. And

35:55

in a certain way, if

35:57

you're a diabetic and you are insulin

35:59

resistant or an obese person and

36:01

you are insulin resistant, and you're a

36:04

hyper secreting insulin, it's

36:06

kind of working against you

36:08

because it's a reverberating system

36:10

that's making the insulin resistance

36:12

aggravated. So one of the big things

36:14

that we've forgotten is that insulin, I told

36:16

you there are two problems in diabetes. One

36:19

is you don't make enough insulin,

36:21

the other is your insulin resistance. You

36:23

need to attack both problems. And

36:25

the paper that I recently published, which

36:27

is a perspective in Lancet diabetes, And

36:30

the chronology was to bring people

36:32

back to, look, we're focusing on obesity

36:34

and weight loss and we should. But

36:37

we need to remember that we

36:39

still have a genetic cause for

36:41

the insulin resistance. You go back

36:43

to 1950, the incidence of

36:45

diabetes was 2%. I've seen even

36:47

data that says it was 1 %

36:49

as recent as 1970. It's very

36:51

low. Yeah. But these people were

36:53

all lean and they're insulin

36:55

resistant. So there's a genetic cause

36:58

of the insulin resistance. And you think,

37:00

Ralph, that the greater genetic effect

37:02

is on the insulin resistance side

37:05

or on the beta -cell fatigue side?

37:07

Both. Okay. So let's tackle each.

37:09

Since you started with insulin resistance, let's

37:11

go there. Let's talk about what

37:13

we know about the genetics of

37:15

insulin resistance. That's

37:17

easy. Nothing. Truly

37:20

nothing. I joke. Let's

37:22

say 20 years ago, we

37:24

got involved in one of the biggest

37:26

genetic studies called the Vega study. Veterans

37:28

Administration Genetic Epidemiologic Study,

37:32

and we were convinced that we were one of

37:34

the people to do the first GWAS studies,

37:36

that we would define all the genes that are

37:38

responsible. Well, we were

37:40

not very successful. Even if

37:42

you took the subset of people

37:44

with type 2 diabetes who

37:46

were lean and you compared them

37:48

to people who were lean

37:50

and non -diabetic versus obese and

37:52

diabetic. A GWAS was not able

37:55

to identify a signal in

37:57

those three cohorts? We identified several

37:59

and remember their associations.

38:01

Of course. And they're in non -coding

38:03

regions, the TCF7LT2 gene.

38:06

We found that, but that had

38:08

already been described by Dr.

38:10

Michael Stern in San Antonio many

38:12

years before. So we repeated

38:14

what Michael showed, and other people have

38:16

shown that. So there are a number

38:18

of associations. Again, if

38:21

you ask me how many

38:23

genes have we truly established

38:25

that are really important in terms of

38:27

causing type 2 diabetes, I

38:29

would say very, very few. I know the

38:31

genetics people out there probably hate this, and

38:33

they'll say that we can put together a

38:35

genetic score. But when they talk

38:37

about a genetic score, it's not

38:39

that they've causally associated a gene

38:42

with diabetes. an association. It's an

38:44

association. We have a whole

38:46

different approach. If you want, I can tell

38:48

you what we're doing that may give some

38:50

insight. And then people have started

38:52

to think about rare diseases that maybe

38:54

the problem is in one family

38:56

you have this particular genetic

38:59

mutation. Another family you have

39:01

a different genetic mutation. A third

39:03

family, a different genetic mutation. And

39:05

then when you do the GWAS

39:07

study, you got this mixture of

39:09

individual genes. What about the phenotype?

39:11

That's the answer. I've taken care

39:13

of a couple of patients with

39:15

type 2 diabetes who are very

39:17

lean, including one

39:19

patient whose body

39:22

fat by DEXA

39:24

was about 8%. For

39:26

people listening, that is insanely

39:28

lean. Very lean. So you

39:30

take an individual whose body

39:32

fat is 8 % and yet they

39:34

have type 2 diabetes. The

39:37

first thing that comes to my mind is a

39:39

lipodystrophy. Is this

39:41

an individual whose

39:43

adipose tissue is

39:45

the problem? In other

39:47

words, they're not able to

39:49

assimilate enough excess nutrient

39:51

i .e. glucose into the

39:54

fat cell and so they're

39:56

undergoing the toxicity associated

39:58

with an insufficient reservoir. Is

40:00

that what could be the causal...

40:02

Not that I can tell you what's

40:04

causing the lipodystrophy, but is the

40:06

lipodystrophy the issue that's driving the

40:09

diabetes? The answer to that

40:11

is it's very clear that

40:13

lipodystrophy can cause diabetes. This

40:15

is, I would say, a very,

40:17

very rare and unusual cause, but

40:19

well -established. But you're saying that's

40:21

not what would explain 1 % of

40:23

diabetics. No, no. Jerry Showman has

40:25

done some beautiful work in this

40:28

area. So it's unequivocal that lipodystrophic

40:30

people, because their fat cells can't

40:32

take up the fat, it ends

40:34

up in your myocardium, cause heart disease. Ends

40:36

up in the beta cells. Ends in your beta

40:38

cell in the muscle. But that's

40:40

a very, very small percentage.

40:43

So the basic genetic etiology of

40:45

the insulin resistance, the PPAR

40:47

Gamer Gene has been associated. There are

40:49

about seven or eight genes. There's

40:51

a recent I think it's

40:53

in Nature Genetics by Brown, where

40:56

they've identified eight. And again,

40:58

they're associations. Except I

41:00

would say the P -pargamic gene, that is

41:02

pretty clear, that's a causal. Did Mitch Lazar

41:04

do some of this work? He's worked

41:06

in this area, but again... It's a long

41:08

list of folks at this point. Yes.

41:10

The number of genes that have been described,

41:13

the other thing people said, well, maybe there

41:15

are 20 genes involved, each giving a

41:17

small component. And that's why it's so difficult. Well,

41:20

all of these hypotheses have been

41:22

difficult to approve. And the simple

41:24

fact is, we don't understand the

41:26

genetic basis. In part...

41:28

diabetes, in my opinion, is a

41:30

very poor phenotype. Diabetes

41:33

is a very heterogeneous disease. So

41:36

when we talk about diabetes,

41:38

if that's your phenotype, it's

41:40

not surprising to me that

41:42

it's going to be difficult to define

41:44

genes that are related to

41:46

diabetes. So what I'm going to

41:48

tell you about, I don't want to

41:50

take the credit for this. So one

41:52

of the people in my division, Dr.

41:54

Luke Norton, working with Steve Parker at

41:56

Michigan, I'm involved because I'm doing the

41:58

insulin clamp studies. We're taking

42:00

as a phenotype muscle

42:03

insulin resistance. This is

42:05

a very, very specific

42:07

phenotype. This is

42:09

not diabetes. The ominous

42:11

octet, my pathophysiology, that's

42:13

eight problems, okay? This

42:16

is muscle insulin resistance. I'm

42:18

gonna do an insulin clamp now. And

42:20

then I'm gonna do a muscle

42:22

biopsy before I do the insulin clamp.

42:25

And I'm going to do a muscle

42:27

biopsy at the end of the insulin

42:29

clamp. And what happens? During

42:31

the insulin clamp, I know exactly how

42:33

sensitive or resistant you are to insulin.

42:35

I've got the most definitive phenotype in

42:37

the world. No one get this kind

42:39

of phenotype. And now what do I

42:41

see? An enormous amount of

42:43

chromatin opens up. This is

42:46

the epigenetic component. Genes

42:48

in the chromatin area that you're

42:50

never ever going to see in

42:52

the basal state. And that's why

42:54

we think... a hypothesis now that

42:56

why it's been so difficult with

42:58

all of these GWAS studies to

43:01

identify genes that are associated with

43:03

diabetes. And now we're starting

43:05

to see diabetic people and non -diabetic

43:07

people. We're starting to see some

43:09

associations which we think now are causal

43:11

and we can relate to the

43:14

insulin resistance with the clamp. Let's

43:16

just pause there for a second,

43:18

Ralph. I want to make sure everybody's

43:20

following what you're saying. You're saying,

43:22

look. One of the challenges of having

43:24

a disease that isn't perfectly, perfectly

43:26

clearly defined, where every single member of

43:28

the class that has the disease

43:30

looks exactly the same, the

43:32

word for that is heterogeneous. So

43:34

let's take an example where the disease is very

43:36

heterogeneous. Sickle cell anemia.

43:38

Correct. Everybody who has sickle

43:41

cell anemia from a pathophysiology

43:43

standpoint is identical. Correct. And

43:45

guess what? There's a single

43:47

mutation that defines the disease. Because

43:50

you have a single gene that

43:52

defines the disease, one gene mutated

43:54

produces one change in one base

43:56

pair that changes one amino acid

43:58

that changes the property of the

44:00

hemoglobin molecule and everybody looks the

44:02

same. But you're saying, Peter, it's

44:04

totally different. With type 2

44:07

diabetes, we have some people that are thin,

44:09

some people that are fat, some people that have

44:11

lots of insulin resistance in the muscle, some

44:13

people that don't seem to have much, but it's

44:15

all in the liver. I want to make

44:17

sure we define the octet, the ominous octet. But

44:19

if that's the case, Why would you ever

44:21

expect to find a simple genetic answer? By definition,

44:23

it's going to be a mess. Absolutely. And

44:26

so if you don't have a

44:28

very definitive phenotype, it's going to be

44:30

difficult. But the implication, by the

44:32

way, is any physician who approaches

44:34

a patient with type 2 diabetes as

44:36

a single entity is going to

44:38

be providing suboptimal care. Yes. I've been

44:40

fighting for 20 years to convince

44:43

people you need to start with combination

44:45

therapy from the beginning. Finally,

44:47

2022, the American

44:49

Diabetes Association has made a

44:52

comment, and for the first time,

44:54

suggests that you should consider starting with

44:56

combination therapy. We can talk about therapy

44:58

to talk about the therapies in detail,

45:00

but yes, you have to take a

45:02

precision medicine approach to type 2 diabetes,

45:04

which begins by trying to identify which

45:06

phenotype your patient is. Before

45:08

we continue, I just want to make

45:10

sure that everybody understands it's Luke Norton

45:12

and Steve Parker, and they're the brain

45:14

child. I'm involved, I understand the disease,

45:16

we're doing the insulin clamps, we're giving

45:18

them the phenotype, and they're doing

45:20

single cell. It turns out there are

45:22

10, 12 different types of cells within the muscle. So

45:25

we tend to think the muscle, oh,

45:27

there's a myocyte, that's the problem. But it's

45:29

probably cells also talking to each other,

45:31

making it even more complex. So

45:33

we're at an early stage

45:35

in the development, but we're enthusiastic

45:38

we really have not discovered these genes.

45:40

So we think that epigenetics are

45:42

important and this is part of the

45:44

epigenetic phenomenon. We'll see where it

45:46

takes us, but we're pretty excited about

45:48

these findings. Let's go back

45:50

to the ominous octet. Make sure I have that

45:52

defined and all our listeners do. So

45:55

in 2008 at the Banting

45:57

Lecture at the American Diabetes

45:59

Association, the title of

46:01

the Banting Lecture was from the Triumvirate

46:03

to the Ominous Octet. So what

46:05

was the triumvirate? I got the

46:07

Young Investigator Award, the Lilly Award from

46:10

the ADA in 1987. So

46:12

the triumvirate was very simple.

46:14

The beta cell, it fails. Insulin

46:17

resistance in the muscle. When you ingested

46:19

a meal, the muscle didn't take up

46:21

the glucose because you're insulin resistant. And

46:24

insulin resistance in the liver. When

46:26

you ate a meal, insulin didn't

46:28

shut down the liver. So that

46:30

was the triumvirate. So from the

46:32

triumvirate to the ominous octet, we

46:34

needed to add five more players.

46:37

So who were the new five players?

46:40

So number four on the list was

46:42

the fat cell, and a very

46:44

deserving guy. So the fat

46:46

cell is your friend initially. You

46:49

overeat, you take in excess calories, you

46:51

store them in the fat cell that can't

46:53

hurt you there. But if you keep

46:55

expanding those fat cells, the fat

46:57

cells become very, very resistant

46:59

to the anti -lipolytic effects of

47:01

insulin. And now you start to

47:03

pour fat out into the

47:05

bloodstream. We've shown this is a

47:07

big interest to... Very counterintuitive.

47:09

Counterintuitive. Not that we should mire

47:11

ourselves in teleologic things. Do

47:13

you have a sense of why?

47:16

Yeah, so the insulin signaling system and

47:18

multiple early steps become severely impaired.

47:20

And when you get insulin resistance in

47:22

the glucose metabolic pathway, there are

47:24

changes that alter the cell metabolism. So

47:26

you become very resistant to insulin's

47:28

anti -lipolytic effect. And so now, if

47:31

you look at people who are obese

47:33

or people who have type 2

47:35

diabetes, their plasma FFA levels

47:37

are very, very high. And

47:39

those FFA levels, and this is

47:41

lipotoxicity, and we've got a long

47:43

history of studying this, high

47:46

FFA levels impair insulin secretion.

47:48

High FFA levels cause insulin

47:50

resistance in the muscle. High

47:53

FFA levels cause insulin

47:55

resistance in the liver.

47:57

high FFA levels impair

47:59

the insulin signaling transduction

48:01

system. And in fact,

48:03

one of my previous fellows

48:05

who's now back with me

48:07

here at UT, Dr. Belfort

48:10

was the first author on

48:12

this paper showing that just

48:14

physiologic rises in the plasma

48:16

FFA literally obliterate the insulin

48:18

signal transduction system, which is

48:20

the first step in glucose

48:22

metabolism. I always thought that

48:24

the reason we saw high

48:26

free fatty acids in people

48:28

with type 2 diabetes was

48:31

not because the fat cells

48:33

were undergoing more lipolysis, but

48:35

because the fat cells were

48:37

themselves becoming resistant to insulin

48:39

and not able to take

48:41

up fat. So same

48:43

net effect, but I was kind of

48:45

drawing the arrow of causality in the other

48:47

direction. The arrow is more on the

48:49

other side. The fat is pouring out fat.

48:51

And you can show that the lipolytic

48:54

enzymes are all resistant to insulin. We've shown

48:56

this, other people have shown it. So

48:58

these elevated FFA levels are a disaster. So

49:00

the fat cell initially is your friend.

49:02

This is your friend who goes to foe.

49:04

Then it becomes a bad guy. So

49:06

that's number four. Number five is the gastrointestinal

49:08

tract. And of course we'll, I'm sure

49:10

talk more about this when we talk about treatment,

49:12

but when you eat a meal, you

49:14

release two incretin hormones. GLP1

49:17

and GIP, glucaon -like peptide

49:19

1 and glucose -dependent insulin trophic

49:21

polypeptide. Those two incretin hormones,

49:23

when you eat a meal,

49:25

account for about 70 %

49:27

of the insulin that's released

49:29

in response to the meal. So

49:32

now, what is the problem? Is

49:34

the problem that you

49:36

don't release enough GLP1 and

49:38

GIP, or is it

49:40

that your beta cell is refractory to the

49:42

GLP1 and GIP? Well, it's the later.

49:45

Let's say that again, Ralph. I want to

49:47

make sure people understand this. And the

49:49

reason it's important is obviously everybody listening to

49:51

us right now is very familiar with

49:53

drugs like semi -glutide and terzepatide. But I

49:55

want people to understand why those drugs were

49:57

developed. And of course, semi -glutide is already

49:59

probably what the third generation of it

50:02

anyway. So when we go back in time,

50:04

we'll understand why people try to develop

50:06

these drugs. But just say that again. So

50:08

you eat your meal, GIP,

50:10

GLP -1 are increased. And they come

50:12

out normally. Yep. That's not the problem.

50:14

And they're telling the beta cell,

50:16

hey, make more insulin. Beta cells deaf,

50:18

not listening. It's resistant to

50:20

the GLP1 and GIP. And he should

50:22

be responding to 70 % of his

50:24

input should come from that signal.

50:26

70 % of the insulin that's going

50:28

to come out is dependent on that

50:31

GLP1 and GIP. So you can

50:33

imagine that that's a huge problem at

50:35

the level of the beta cell

50:37

in terms of the defect in insulin

50:39

secretion. And tell me, why is

50:41

it mechanistically that the beta cell becomes

50:43

deaf to GLP1 and GIP. I

50:45

don't know that we know the answer

50:47

to that. So it's just another

50:49

horrible piece of this puzzle where everything

50:51

starts to work against the patient.

50:53

Yes. So this is an area, of

50:55

course, intense investigation, but the

50:57

clinical counterpart of this, as you've already

50:59

mentioned, the drugs that are out

51:01

there, the GLP1 receptor agonist, what I'm

51:04

doing is I'm giving you a

51:06

pharmacologic dose of GLP1, and I'm overcoming

51:08

the resistance at the level of

51:10

the beta cell. Now, there's another component

51:12

to this that we'll get to, and

51:15

that's glucotoxicity. And these

51:17

are studies that were done by Jens Tolts and

51:19

the group in Denmark. They

51:21

took people and they infused

51:23

GIP. We're talking about GIP. And

51:26

you don't respond to the GIP. These

51:28

are type 2 diabetics. And then they intensively

51:30

treated them with insulin and lowered their

51:32

glucose. And then when they come

51:34

back with the GIP, you release

51:36

a normal amount of insulin.

51:38

So this is a glucotoxic

51:40

effect. So you ask me,

51:42

mechanism. So we know that at

51:44

least for the GIP, the

51:47

glucotoxicity is impairing the ability of

51:49

the beta -cell to respond to

51:51

the GIP. But not necessarily

51:53

GLP1. No, no. And that doesn't

51:55

correct the GLP1 problem. So

51:57

there's true resistance still, even though

52:00

I normalize the glucose in

52:02

terms of GLP1. So this incrotin

52:04

axis, the gut, is a

52:06

very important endocrine organ. And that's

52:08

number five in the ominous

52:10

octet. Number six in the ominous

52:13

octet is the alpha cell.

52:15

I would say the father of

52:17

hyperglucogonemia, this is Dr. Roger

52:19

Unger in Dallas. He was one

52:21

of the very first people

52:23

to show that diabetics had very

52:26

high glugon levels. And

52:28

glugogon Tell people what glugogon does.

52:30

Yeah, glugon, it drives hepatic glucose

52:32

production. So if your glucose gets

52:34

too low, your alpha cells will

52:36

release glucagon. So the alpha cell can

52:38

sense the glucose. And

52:40

so if you're hypoglycemic, this is

52:43

an important defense mechanism. You

52:45

release glucagon, that stimulates your

52:47

liver, and the glucose production goes

52:49

up, it returns your glucose to

52:51

normal. But a diabetic already has

52:53

a high glucose. We don't

52:55

want high glucagon levels.

52:57

So paradoxically, there's very high

52:59

glucagon levels in the diabetic. And

53:01

those high glugon levels are very

53:04

important contributor to the hepatic insulin

53:06

resistance because they're driving the liver

53:08

to make glucose. And sorry, just

53:10

to make sure that I'm embarrassed

53:12

to say I forget this from

53:14

biochemistry. Is it driving the liver

53:17

to make glucose out of, for

53:19

example, glycerol, amino acids or other

53:21

things? Gluconeogenic pathway and glycogenolosis. Acutely.

53:25

So if I acutely give you a glugon,

53:27

the first thing that happens you break down glycogen.

53:29

But very quickly you... rid of all the

53:31

glycogen that's in the liver. And

53:33

so chronically now you're running on

53:35

gluconeogenesis. But glue gun stimulates both

53:37

pathways. And does it also

53:39

drive hepatic glucose output? Yes. Or does

53:41

it just drive the creation of

53:43

glucose? No, no, no. In absolute terms.

53:45

It increases hepatic glucose output as

53:47

well as gluconeogenesis. Yes. And that's a

53:49

important reason why you have fasting

53:51

hyperglycemia. So when you wake up in

53:53

the morning... Yeah, and your blood

53:55

sugar is 110 milligrams per deciliter. That's

53:57

the liver. And part of that

53:59

is because your liver is intrinsically resistant

54:01

to insulin. Part of

54:03

it is because the liver

54:06

is now responding to the

54:08

glucagon and producing an excess

54:10

amount of glucose, both through

54:12

gluconeogenesis and through glycogenolosis. Although

54:14

I would say the major

54:16

contributor is the gluconeogenic pathway. Now,

54:19

that gluconeogenic pathway is also turned on

54:21

because fat is coming from the fat

54:23

cell. Remember I told you the FFA

54:25

is high. Yes. Glycerol is coming from

54:27

the fat cell. Yes. We talked about

54:30

some of the work that Jerry did.

54:32

This is Jerry's work showing that glycerol

54:34

coming from the fat cell is an

54:36

important driver of gluconeogenesis. And

54:38

then hepatic fatty acyl CoA levels

54:40

are up because you have all

54:42

this fat pouring in and that's

54:44

activating the enzymes pyruvate carboxylase that

54:46

are driving the gluconeogenic pathway. So

54:48

the metabolic, the actual pathways I

54:50

think are very well worked out.

54:52

So, glue gun, alpha cell, bad

54:54

guy. And so, is the alpha

54:56

cell over -producing glucagon in this

54:58

state? Yes, absolutely. Absolutely. And this

55:00

is really Roger Unger in dialysis.

55:03

And again, why is it over -producing?

55:05

Why is it doing something that

55:07

doesn't make any sense in the

55:09

context of what's happening? And in

55:11

a certain way, this is also

55:13

insulin resistance, because hyperinsulinemia shuts down

55:15

glucagon. And we have very high

55:17

fasting insulin levels in the diabetic,

55:19

okay? Now, what is

55:21

it? What's the sensing mechanism? It's

55:23

counterintuitive. Usually when things go

55:25

wrong, they get attenuated, right? It

55:27

makes sense that the beta

55:29

cell eventually fatigues because that's an

55:31

attenuation of doing something that

55:33

it's getting tired of doing. The

55:36

alpha cell ramping up is

55:38

a little less intuitive. You're

55:40

going to see it gets even worse when we talk about the

55:42

kidney, which is number seven on the list. All right, let's go

55:44

to number seven. Okay, so

55:46

people don't know I'm also board

55:48

certified in nephrology. In the old

55:50

days, I trained as a micropuncturist.

55:53

I used to sit with a

55:55

microscope. I would draw my

55:57

little pipettes out the night before and

55:59

put the little micropipette in the tubules,

56:01

and I collect tubular fluid. What

56:03

I was interested in, and this is when

56:05

I was a renal fellow at the University of

56:07

Pennsylvania, I was interested in

56:09

glucose and phosphate transport. And I

56:11

published the series of acts of the pretty elegant

56:13

papers in the JCI, looking

56:15

at how glucose and what

56:17

regulated glucose in phosphate

56:20

transport. And I knew that

56:22

there was a molecule called fluorescent that

56:24

blocked glucose transport in the kidney.

56:26

And so I took this molecule called

56:28

fluorescent and it blocks glucose transporters.

56:30

There are two transporters in the kidney.

56:33

SGLT2 and SGLT1.

56:36

SGLT2 takes back 90 % of the

56:38

glucose. If it does

56:41

its job, SGLT1 takes back

56:43

the other 10%. And then in

56:45

URI, Even though we

56:47

filter 180 grams of glucose per

56:49

day, no glucose appears in

56:51

the urine. But what I showed

56:53

is that fluorosin, it blocked

56:56

both SGLT2 and SGLT1, it

56:58

blocked glucose transport, and

57:00

it also blocked phosphate transport. And

57:02

I showed that glucose and phosphate

57:04

transport were coupled. When I

57:07

was doing these studies, even though I

57:09

was a nephrology fellow, I had

57:11

previously done my endocrine fellowship at

57:13

the NIH in Baltimore City Hospitals, I

57:15

had an interest in diabetes and

57:17

I said, this would be a great

57:19

way to treat diabetes. So

57:21

in the old days, we did things

57:23

for science and I published a series of

57:25

four papers in the JCI and I

57:27

never even thought of, to be honest with

57:29

you, of patenting this. I have a

57:31

significant other who said to me one day,

57:34

she said, Ralph, you're one of the

57:36

smartest guys I ever met. And I said,

57:38

yeah, I know that. And she said,

57:40

you're probably the stupidest guy I ever met.

57:42

And I said, why? She said, you

57:44

could have patented this. Drug.

57:46

So I actually worked with Bristol Maya

57:48

Squibb and then AstraZeneca and that

57:50

eventually led to the Dapaglide flows and

57:52

coming to the market. But what

57:54

we showed and this is human by

57:56

which is the first sglt2 inhibitor.

57:59

That's Yes, brand name on that one.

58:01

Uh, Forsiga. Forsiga. Yeah. Canaga flows

58:03

in was next. Ampaglide flows in. Yeah.

58:05

And then Canaglide flows in, Ertuglide

58:07

flows in, do we have a bunch

58:09

of them? They're all very good.

58:11

Basically do the same thing. But what

58:14

we showed was the SGLT -2 transporter

58:16

was markedly up -regulated in the kidney.

58:19

Let's just wrap our heads around this again.

58:21

This is so counter -intuitive. I know. Okay, this

58:23

does not make any sense. I want to

58:25

just bring it back to people listening so

58:27

they understand what we're talking about here. The

58:30

kidney is this massive filtration. Another

58:32

remarkable organ. No offense to the nephrologist.

58:34

Not as remarkable as the liver, but

58:37

every bit is remarkable in terms of... I

58:39

think it's more remarkable than the liver guy,

58:41

so that's okay. Everything

58:43

that's floating through our plasma, our

58:45

kidneys, by the way, they take

58:47

25 % of our cardiac output. So

58:49

it's massive. This organ weighs 2

58:51

% of our weight and takes

58:53

25 % of our cardiac output. Why?

58:56

Because we have to take everything that

58:58

is in our circulation and dump

59:00

it out. And then the kidney has

59:02

to selectively bring back in what's

59:04

normal. This was explained to me, I

59:06

still remember in medical school, as

59:08

the brilliant trick of evolution. Evolution

59:10

was never going to be able

59:12

to predict every toxic thing we might

59:14

encounter and therefore teaching the kidney

59:17

how to spot toxic things and get

59:19

rid of them would have been

59:21

a failed mission. Rather, it was better

59:23

to teach the kidney what was

59:25

absolutely necessary and to discard all other

59:27

things. Three simple ways.

59:29

Yep. So, it's the take everything

59:31

out of your drawer and dump it

59:33

out and only bring back the

59:35

socks and underwear that you need. So,

59:38

glucose, potassium, sodium. You

59:40

name it, chloride, phosphate. All of these

59:42

things get dumped along with everything else. And

59:44

then it knows, I need this much

59:46

glucose. I need this much sodium. I need

59:48

this much potassium. So SGLT2

59:50

does the lion's share of

59:53

this. It takes back 90 %

59:55

of the glucose. And now, so

59:57

here's a diabetic with a very high

59:59

glucose. Right. So my point was SGLT2,

1:00:01

if it had a brain, would say,

1:00:04

oh, You have too much glucose. Turn

1:00:06

off. Turn it off. How about we

1:00:08

just stop reabsorbing all this glucose? But

1:00:10

you said it's the opposite. I told

1:00:12

you earlier it's going to get worse.

1:00:14

It ramps up SGLT2. So as a

1:00:16

doctor, I want the kidney

1:00:18

to dump the glucose out in the

1:00:21

urine. Yeah. But what is the kidney

1:00:23

doing? It's doing the opposite. It's holding

1:00:25

on to the glucose. Even as a

1:00:27

renal fellow, it became clear to me,

1:00:29

this is such a simple way to

1:00:31

treat diabetes. And the fact is,

1:00:33

it's so simple no one thought about it.

1:00:35

The only dumb thing that I did was

1:00:37

I didn't patent it, which I should have

1:00:39

done. I probably never have to write another

1:00:41

NIH grant for the rest of my life.

1:00:43

And then we went on to show, and

1:00:45

in fact, this is the first definitive proof

1:00:47

of the glucose toxicity hypothesis. So

1:00:49

we did all of these studies initially

1:00:51

in animals, and this was all published

1:00:54

in the JCI, and Luciano

1:00:56

Rosetti is one of the fellows at

1:00:58

this time. Actually, Jerry Showman was

1:01:00

a fellow on the papers as well.

1:01:02

And what we showed was that

1:01:04

you could take different types of diabetic

1:01:06

animal models, and you could show

1:01:08

that they're reabsorbing excessive amounts of glucose.

1:01:11

And then if I treated them with

1:01:13

fluorescent, because that's what was available, they

1:01:16

simply pee the glucose out in the urine. And

1:01:18

now all a sudden, their beta

1:01:20

cells started functioning normally. Muscle

1:01:22

insulin sensitivity improved. So

1:01:24

of course, that's wonderful if you're a mouse

1:01:26

or a rat. So we said, well,

1:01:29

what about humans? And so

1:01:31

The original studies actually were

1:01:33

done, there's kind of an

1:01:35

interesting story behind this, but the

1:01:37

initial studies were done with Dapaglyphlosin, and

1:01:40

we showed with just 14 days

1:01:42

of treatment with Dapaglyphlosin, we

1:01:44

markedly lowered the fasting and

1:01:46

postprandial glucose, we improved insulin

1:01:48

sensitivity by 35%, and we

1:01:50

made a major improvement in beta

1:01:52

cell function. Now, the

1:01:54

beauty of this, SGLT2 inhibitors are

1:01:57

only in the kidney. they're not

1:01:59

in your muscle, they're not in

1:02:01

your beta cell. And the

1:02:03

only thing that the SGLT2 inhibitors do makes

1:02:05

you put glucose out in the urine. The

1:02:07

only change in the plasma was

1:02:09

the glucose came down. And now

1:02:11

insulin sensitivity improved and muscle and

1:02:13

beta cell function improved. And this

1:02:16

was the first, now in humans,

1:02:18

even though the original studies were

1:02:20

done in animals, first studies to

1:02:22

show an improvement in the reality

1:02:24

of glucose toxicity. What was interesting,

1:02:26

is that when we started to

1:02:28

work on developing this with BMS

1:02:30

and AstraZeneca, the company decided,

1:02:32

well, we should get some nephrologists

1:02:34

in to see about this story. They

1:02:36

said, look, if you listen to

1:02:38

what Dr. DeFranco says, this will be

1:02:40

a disaster. And they said,

1:02:42

why? Because if you put glucose

1:02:44

in the urine, it will glycosylate the

1:02:47

proteins, then you'll cause kidney damage. And

1:02:49

they actually held up the development

1:02:51

of the SGLT2 inhibitors. And the

1:02:53

way we finally convinced them to

1:02:55

go ahead was that there's a

1:02:57

disease called familial renal glucoseuria. From

1:02:59

day one of their life, they're

1:03:01

picking out tremendous amounts of glucose.

1:03:03

They have perfectly normal kidney function.

1:03:06

How many grams of glucose can be

1:03:08

differentially or extra secreted basically in

1:03:10

the presence of an SGLT2 inhibitor today?

1:03:12

It kind of depends on what

1:03:14

the level your GFR is, but it

1:03:16

could be anywhere from 40 to

1:03:18

60 grams up to 120 grams of

1:03:20

glucose. And the higher would be

1:03:23

in somebody with a higher gradient. Yeah.

1:03:25

The higher the glucose. The higher

1:03:27

the, yeah. Yes. Because you filter more

1:03:29

glucose, then there's more glucose to

1:03:31

be blocked at the level of the

1:03:33

kidney. And these drugs

1:03:35

are very, very good. Now, I

1:03:37

actually, in developing these drugs, as

1:03:40

I said, I'm also an

1:03:42

aphrologist based on the Barry Brenner

1:03:44

hypothesis, I predicted these drugs

1:03:46

would save your kidneys according to

1:03:48

the Brenner hypothesis. And that's

1:03:50

all turned out to be correct. These drugs are

1:03:52

great for the kidney. What I never, ever envisioned

1:03:54

that these drugs were going to save your heart,

1:03:56

yeah. I want to come back to that because

1:03:59

I'm making notes of other things I want to

1:04:01

come back to. And so I want to come

1:04:03

back to, just so you can hear me say

1:04:05

it now and we remember, I want to

1:04:07

come back to combined inhibitors, the SGLT -2,

1:04:09

SGLT -1 inhibitor. I think there's a new

1:04:11

drug. Soda glyphos. Yeah, it does both.

1:04:13

We'll just touch on that. And then I

1:04:15

want to also come back to the

1:04:17

broader, zero protective nature of the SGLT -2s

1:04:20

as documented by the ITP in mice and

1:04:22

then also in the human studies for

1:04:24

cardio protection. But before we do that, we

1:04:26

need to finish the armor. Exactly. Let's

1:04:28

go back to number eight. The brain. So

1:04:30

the brain plays a role in a

1:04:32

somewhat indirect way. So every day

1:04:34

you have your breakfast, your lunch.

1:04:36

I actually eat only once a day,

1:04:38

but at some point you eat

1:04:40

a meal. And at some time during

1:04:42

the meal, I'll say, okay, I'm

1:04:44

hungry. I stopped eating. Why'd you ever

1:04:47

think? Why does that happen? Well,

1:04:49

because there are certain hormones that are

1:04:51

released or inhibited that tell you,

1:04:53

okay, you're satiated, stop eating. Well, one

1:04:55

of the very important ones is

1:04:57

GLP1. That same thing that's increasing insulin

1:04:59

secretion, your brain has become very

1:05:01

resistant to GLP1. When you eat a

1:05:03

meal, amylin comes out. It comes

1:05:05

out in a one -to -one ratio with

1:05:07

insulin. Your brain has become resistant

1:05:09

to amylin. Your brain is resistant to

1:05:11

leptin. So there are a lot

1:05:13

of these inorectic molecules that your brain

1:05:16

has become resistant to. And these

1:05:18

molecules, it's another area of interest of

1:05:20

mine, they work in the

1:05:22

hedonic areas in the brain. So

1:05:24

in the putamen, the prefrontal cortex,

1:05:26

and they tell you to stop eating.

1:05:28

And unfortunately, and this

1:05:31

is the big unknown is what's going

1:05:33

on in the brain, the neurosurgery

1:05:35

is clearly distorted. Not only is

1:05:37

the neurosurgery distorted, one of the

1:05:39

big things that we are interested in,

1:05:41

Dr. Peter Fox and myself at

1:05:43

UT, is if you look at the

1:05:45

gray matter in these areas, in

1:05:47

the areas that are critically important in

1:05:49

regulating your appetite, there's shrinkage of

1:05:51

the gray matter area, okay? And

1:05:53

in these areas, if you do an

1:05:55

insulin clamp, the brain is

1:05:58

insensitive to insulin in your

1:06:00

eye. In obese people, these areas

1:06:02

in the brain with this

1:06:04

abnormal marked increase in glucose uptake.

1:06:07

Incredible finding, who would have thought?

1:06:09

I'm sorry, you're saying that

1:06:11

These are the few areas in

1:06:13

my brain and your brain

1:06:15

that are actually default insulin insensitive.

1:06:17

Yes. Don't take up glucose. Correct. If I

1:06:19

do an insulin clamp. So what is

1:06:22

their fuel source? Lactate? Well, in

1:06:24

response to insulin, they don't take up more

1:06:26

glucose. Oh, okay. I'm sorry. Got it.

1:06:28

Because remember, this is from the Cahill studies.

1:06:30

As long as your glucose is about 50,

1:06:32

your brain is happy. So this is

1:06:35

actually in the evolution of the human

1:06:37

being. This is phenomenal. Because in the old

1:06:39

days, you... not eat, you may slaughter

1:06:41

one of these beasts. Yeah, you're not eating

1:06:43

for days. You're not eating for days. So

1:06:45

your glucose would drop. So if your normal fasting

1:06:47

was 80, if it dropped to

1:06:49

40, you're okay because your brain saturated

1:06:52

it 40. If you got below 40, you're

1:06:54

in trouble. So you have a big

1:06:56

buffer here. But now if I infuse insulin

1:06:58

and your glucose is 80, your brain

1:07:00

doesn't take it up more glucose. It's quote,

1:07:02

insulin insensitive in a certain way. Now,

1:07:05

of course, if you take

1:07:07

people with mild cognitive impairment, There's

1:07:09

been some experiments that actually

1:07:11

suggest in these people, insulin infusion

1:07:13

can transiently improve glucose uptake,

1:07:15

but presumably that's because they're insufficiently

1:07:17

getting glucose in the disease

1:07:19

state. Yes, this has been postulated.

1:07:21

This also suggests that there's

1:07:23

brain insulin resistance, which

1:07:25

is, I'd say, an interesting concept

1:07:28

and may play some role in

1:07:30

this neurocognitive dysfunction and Alzheimer's whole

1:07:32

different story that's in evolution. But

1:07:34

to come back to the ominous

1:07:36

octet now, If you overeat, what

1:07:38

happens? You gain weight. And

1:07:40

when you gain weight, you

1:07:43

become insulin resistant, severely insulin

1:07:45

resistant. That's lipotoxicity. And we've

1:07:47

done studies in both directions. I

1:07:50

can put an IV and I

1:07:52

can infuse an emulsion of free fatty

1:07:54

acids. And I can show within

1:07:56

two to four hours, I

1:07:58

induced severe insulin resistance in the

1:08:00

muscle, in the liver, and

1:08:02

I markedly impaired beta cell function.

1:08:05

And then... this drug in the United

1:08:07

States, but there's a drug that's available

1:08:09

in Europe, and I have an IND

1:08:11

to use it. It's called the cipamox. It

1:08:14

inhibits lipolysis. It's like

1:08:16

SGLT2 inhibitor. The only thing to do

1:08:18

is block glucose reabsorption in the kidney.

1:08:21

Cipamox, all it does is do block

1:08:23

lipolysis. It lowers your FFA level. And

1:08:26

we've done this. Does it result

1:08:28

in any meaningful... increase in adiposity or

1:08:30

is it so subtle that you

1:08:32

don't notice it? Over 12 days, no

1:08:34

change in adiposity, huge improvement in

1:08:36

insulin sensitivity and muscle. Why is it

1:08:38

not approved in the US? I

1:08:41

don't know the company that developed it

1:08:43

in Europe ever tried to get it approved

1:08:45

in the US. It's, I

1:08:47

would say, modestly

1:08:49

effective in lowering triglycerides.

1:08:51

And we have phenofibrates which are much

1:08:54

more effective. So that may be the

1:08:56

reason. But the triglyceride and the FFA

1:08:58

are not the same thing. No. But

1:09:00

that's the reason why it's approved in

1:09:02

Europe. But if you lower the FFA,

1:09:04

that's the precursor for triglyceride synthesis. So

1:09:06

it has an effect to lower the

1:09:08

triglycerides. But the key thing is if

1:09:10

you lower the FFA, and we did

1:09:13

this for 12 days, we did it

1:09:15

in both obese people and in diabetic. You

1:09:18

markedly improve insulin sensitivity

1:09:20

in the muscle. If using

1:09:22

MRI, you can measure

1:09:24

muscle fat goes down dramatically

1:09:26

and correlates with the

1:09:28

improvement in insulin sensitivity. We

1:09:30

also measured ATP generation

1:09:32

because this issue is clearly

1:09:34

mitochondrial dysfunction if you're

1:09:36

diabetic. That's unequivocal. The

1:09:38

controversy is the mitochondrial dysfunction

1:09:40

causing the insulin resistance

1:09:42

or is the insulin resistance

1:09:45

causing the mitochondrial dysfunction. So

1:09:48

in this study that we

1:09:50

did, when we lowered the

1:09:52

FFA and lowered the muscle

1:09:54

lipid content, we saw about

1:09:56

a 50 % improvement in

1:09:59

ATP generation, mitochondrial ATP generation. So

1:10:02

at least this says that

1:10:04

part of the mitochondrial dysfunction

1:10:06

is secondary to the lipotoxicity

1:10:08

and insulin resistance. But

1:10:10

this still remains, I would

1:10:12

say, a controversial topic. Clearly,

1:10:15

it is mitochondrial dysfunction. If

1:10:17

you can improve it, that's going

1:10:19

to improve insulin sensitivity. Is

1:10:21

there anything that improves mitochondrial function

1:10:23

more than aerobic exercise training? Peoglidazone.

1:10:26

The drug that I can't get

1:10:28

people to use, which is a

1:10:30

phenomenon. By activating p -pargamma, it

1:10:32

does a lot of good things.

1:10:34

And one of the important things

1:10:36

that it does, it has a

1:10:38

huge effect to improve mitochondrial dysfunction. And

1:10:41

it has direct effects. It

1:10:43

works directly through p -pargamma to

1:10:45

do this. And it also binds

1:10:47

directly to the mitochondrial pyruvate

1:10:49

carrier. and that influences flux through

1:10:52

the mitochondrial chain. Why don't

1:10:54

people use this drug today? Huge

1:10:57

misconceptions. I

1:10:59

guess we'll talk about therapy. We'll

1:11:02

come back to it. As

1:11:04

part of my triple therapy regimen,

1:11:06

I use a GLP1 receptor

1:11:08

agonist, I use peel glidazone, and

1:11:10

I use an SGLT2 inhibitor. There's

1:11:13

a fourth good drug and that's

1:11:15

metformin. And you might ask, well, why

1:11:17

is Metformin number four on my

1:11:19

list of good drugs, since I single

1:11:21

-handedly brought Metformin to the United States

1:11:23

in 1995? No other

1:11:25

endocrinologist involved in this. 1995

1:11:27

Metformin was a revolutionary drug.

1:11:30

Why? We had insulin and cell

1:11:32

foam, you risk. So now

1:11:34

we had a drug that really could work.

1:11:36

It's still a very good drug. And of

1:11:38

course, it's very cheap. It's $5 a month

1:11:40

in the state Texas, but we have much

1:11:42

better drugs. Peoglidazone causes

1:11:44

weight gain. Now, here's

1:11:46

the problem. It'll become very obvious.

1:11:49

We talk about these paradoxes. The

1:11:51

more weight gain, the greater the drop

1:11:53

in A1c. The more weight gain, the

1:11:55

greater the improvement in insulin sensitivity. And

1:11:57

is it fat gain specifically? No.

1:12:00

I'll come back to that in a second.

1:12:03

It is fat weight gain, and I

1:12:05

also believe muscle weight gain. The more weight

1:12:07

gain, the greater the improvement in beta

1:12:09

cell function. The more weight gain, the greater

1:12:11

the drop in blood pressure. The more

1:12:13

weight you gain, the greater the drop in

1:12:15

triglycerides. The more weight you gain, the

1:12:17

greater the rise in HDL cholesterol. Sounds like

1:12:19

terrible drug. So here's another one of

1:12:21

those paradoxes. Why? We know if you overeat

1:12:23

and gain weight, that's a disaster. But

1:12:26

with peal glidazone, the more weight you

1:12:28

gain, everything gets better. What peal glidazone

1:12:30

does is it shifts weight around in the

1:12:32

body. In my opinion, it's the best

1:12:34

drug for treating Nash. No drug is

1:12:36

going to beat peal glidazone. the pharmaceutical companies,

1:12:39

if you had to go up against

1:12:41

pial glidazone, all these Nash drugs, I

1:12:43

don't believe you can beat pial glidazone. What's

1:12:45

the brand name for pial glidazone? Actose. As

1:12:48

I said, there's this paradox. So

1:12:50

why do you gain weight? Pial

1:12:52

glidazone, it redistributes fat in the

1:12:54

body. It gets it out of

1:12:57

the muscle, puts it in subcutaneous tissue.

1:12:59

Gets it out of the liver, puts it

1:13:01

in subcutaneous tissue. Gets it out of

1:13:03

your beta cells, put it in subcutaneous tissue.

1:13:05

That's not gonna make you gain weight.

1:13:07

the richest density of P -pargamma receptors in

1:13:09

the hypothalamus. So when I activate

1:13:11

these P -pargamma receptors in the hypothalamus,

1:13:13

you eat, okay? It makes you hungry.

1:13:16

That's got nothing to do with

1:13:18

redistributing the fat in the body,

1:13:20

except they parallel each other in

1:13:22

association. And so you see

1:13:24

the weight gain and people say, oh,

1:13:26

that's bad. But what's really doing the

1:13:29

thing is this recycling and moving the

1:13:31

fat around. The other negative

1:13:33

thing about P -olidazone is it causes

1:13:35

fluid retention. So, people

1:13:37

have associated fluid retention with

1:13:39

heart failure. Now, why

1:13:41

do you get fluid retention?

1:13:44

Again, people do not understand. Pioglidazone,

1:13:46

the only thing, the only

1:13:48

drug that is a true insulin

1:13:50

sensitizer is Pioglidazone. Metformin is not

1:13:53

a true insulin sensitizer. That total

1:13:55

misconception. Pioglidazone, that

1:13:57

insulin signaling defect that I told

1:13:59

you about, Pioglidazone corrects that defect.

1:14:01

It's incredible. We kind of glossed

1:14:03

over this. We're going to spare

1:14:05

people the details, but it's probably

1:14:08

worth just reminding people. Insulin

1:14:10

binds to the insulin receptor

1:14:12

that's outside the cell. That's a

1:14:14

kinase receptor, correct? There are

1:14:16

three tyrosine molecules, and they have

1:14:18

to be phosphorylated. These are

1:14:20

studies done, Ron Kahn and

1:14:22

other people in Boston. You mutate

1:14:24

one of those tyrosines, you become

1:14:26

a little insulin resistant. You mutate

1:14:28

two of them, you become moderately

1:14:30

insulin resistant. You mutate three of

1:14:32

them, you're severely insulin resistant. Insulin

1:14:34

binds to the receptor. Okay, that

1:14:36

happens normally in diabetics. We showed,

1:14:38

there's no problem there. Then IRS1,

1:14:40

insulin receptor substrate one. Which is

1:14:42

inside the cell, comes up. Yes.

1:14:45

It interacts with the insulin receptor

1:14:47

and it gets phosphorylated on

1:14:49

the same three tyrosine molecules. And

1:14:52

then you activate PI3 kinase, AKT.

1:14:54

We could add some more molecules

1:14:56

in here. But this is the

1:14:58

insulin signaling pathway. That's

1:15:00

the pathway that... the earliest defect that

1:15:02

you can show in diabetics is in

1:15:04

that pathway. And if

1:15:06

I recall, isn't this

1:15:08

where Jerry argued that

1:15:10

the intramiocellular lipid was

1:15:13

creating the defect in

1:15:15

that pathway, the accumulation

1:15:17

of intramiocellular lipid? So what Jerry

1:15:19

has shown very elegantly is

1:15:21

that there are certain lipids, DGAT,

1:15:23

and it's a specific DGAT.

1:15:25

They're like several types of DGAT

1:15:27

molecules, which has confused things.

1:15:29

So he's shown there's a specific

1:15:31

one of the D -gats that

1:15:34

activates these atypical PKC molecules,

1:15:36

and that serine phosphorylates the insulin

1:15:38

receptor. When you serine phosphorylate

1:15:40

the molecules in that pathway, it

1:15:42

inactivates them, okay? And so he's done

1:15:44

these very nice elegance studies, both

1:15:46

in peripheral muscle and in the liver,

1:15:48

showing that this plays a very,

1:15:51

very important role in the insulin resistance.

1:15:53

This is part of the lipotoxicity.

1:15:55

I don't believe that this is the

1:15:57

genetic basis. genetic

1:15:59

etiology. You get fat and you

1:16:01

start putting fat everywhere. This is

1:16:03

very important, critically important. That was

1:16:05

when he gave his banting lecture

1:16:07

and I might say I am

1:16:09

delighted that I got to write

1:16:11

his letter of nomination for the

1:16:13

banting lecture. He was incredibly deserving.

1:16:15

He's done phenomenal work in this

1:16:17

area. But that was his banting

1:16:19

lecture and you're right. Very, very,

1:16:21

very important mechanism of insulin resistance.

1:16:24

And so given that that's both

1:16:26

a very important and very common,

1:16:28

pathway towards insulin resistance, bringing it

1:16:31

back to P -par gamma. P -par

1:16:33

gamma is part of the pathway. It's

1:16:35

part of the IRS1, P -par

1:16:38

gamma, PI3K, GLUT4, bring the

1:16:40

glucose in the cell. In other

1:16:42

words, if people don't want

1:16:44

to get mired down in this,

1:16:46

which is totally understandable, insulin

1:16:48

hits a receptor. That receptor kicks

1:16:50

off a cascade. that

1:16:52

ultimately results in a little tube,

1:16:54

like a little straw that

1:16:56

goes into the cell surface that

1:16:59

allows glucose to freely flow

1:17:01

in, in its gradient. Remember that

1:17:03

same pathway also activates nitric

1:17:05

oxide synthase. That's right. Generates nitric

1:17:07

oxide. And that's why we

1:17:09

see in patients with insulin resistance,

1:17:11

even if glucose is controlled,

1:17:13

cardiovascular disease is still up. Very

1:17:16

important. Yeah, very important point.

1:17:18

So back to actose. So

1:17:20

what does it do? It

1:17:22

activates that signaling pathway. You

1:17:24

generate nitric oxide. Now

1:17:26

you vasodilate. That's why the blood

1:17:28

pressure drops. When you vasodilate, so

1:17:30

I'm a nephrologist, I understand this

1:17:32

very clearly. Anytime you end up

1:17:35

refuse the kidney, you hold on

1:17:37

a salt mortar. You become a deminus.

1:17:40

And so people associate fluid

1:17:42

retention in edema with

1:17:44

heart failure. So we did

1:17:46

the definitive studies published in Diabetes

1:17:48

Care in 2017. People just

1:17:50

don't read. So we took people

1:17:52

who had diabetes, and we treated

1:17:54

them with peel -glitazone. And

1:17:56

then using NMR very, very

1:17:58

sophisticated techniques, what we

1:18:01

showed is peel -glitazone markedly improved

1:18:03

myocardial blood flow. Now, these numbers

1:18:05

are gonna blow your mind

1:18:07

away. Myocardial insulin sensitivity

1:18:09

with PET and fluorideoxyglucose improved

1:18:11

by 75%. Your heart, we showed

1:18:13

this before, is severely insulin

1:18:15

resistant. I came pretty damn close

1:18:17

to normalize insulin sensitivity in

1:18:19

your heart. Now, since we're doing

1:18:22

the insulin clamp with Tradioglucose,

1:18:24

you can track it. 74 %

1:18:26

improvement in skeletal muscle insulin sensitivity.

1:18:28

It's the same. Exactly the

1:18:30

same. If you look at

1:18:32

ejection fraction, it went up by

1:18:35

5 % to 10%. Not down. It

1:18:37

went up. If you look

1:18:39

at every measure of diastolic dysfunction, E

1:18:42

over A, E over E prime,

1:18:44

LV, peak filling pressures, et cetera,

1:18:46

cardiology people understand this. The

1:18:48

point is, whether you're looking at

1:18:50

systolic function or diastolic function,

1:18:53

it all got better. It's a

1:18:55

victim of maybe not so

1:18:57

nuanced thinking about the drug. Now,

1:18:59

the critic would push back and say, okay,

1:19:01

Ralph, but don't we have better drugs? Like, I

1:19:03

mean... No drug that corrects insulin resistance. Metformin

1:19:06

is not an insulin sensitizer, and

1:19:08

people keep going back to this. I

1:19:10

brought metformin to the US in

1:19:12

1995. I know this. I

1:19:14

did all the mechanism of action studies.

1:19:16

What we showed was the insulin

1:19:18

clamp. The drug absolutely does not improve

1:19:20

insulin sensitivity. So let's talk about

1:19:22

metformin. Everybody wants to know if metformin

1:19:25

is giroprotective, but let's just remind

1:19:27

people metformin inhibits complex one of the

1:19:29

electron transport chain. Is that a

1:19:31

given? Yes. I'd say this is still

1:19:33

controversial in high doses for sure.

1:19:35

Yes. And the kind of

1:19:38

doses you see with giving

1:19:40

metformin, I would say somewhat equivocal.

1:19:42

Is the belief that metformins

1:19:44

efficacy in diabetes is through reducing

1:19:46

hepatic glucose output? That is

1:19:48

100 % true. Okay, and what's

1:19:50

the mechanism by which it reduces

1:19:53

hepatic glucose output? Inhibiting the

1:19:55

mitochondrial chain and inhibiting gluconeogenesis. Well,

1:19:57

for sure it inhibits gluconeogenesis. Metformin

1:20:00

gets in the cells through the

1:20:02

organic cation transporter. The organic cation

1:20:04

and ion transporter doesn't exist in

1:20:07

muscle. It can't possibly

1:20:09

be an insulin sensitizer in muscle.

1:20:11

You're asking the drug to do

1:20:13

something that's impossible. Does it get

1:20:16

into muscle mitochondria? No, it doesn't

1:20:18

get into muscle at all. Why

1:20:20

does lactate go up when people

1:20:22

are taking metformin? Level of the

1:20:24

liver. It's interfering with aerobic metabolism.

1:20:26

There's a block. This is very

1:20:28

important. I have erroneously always believed, so

1:20:31

I'm really happy to be corrected. I love

1:20:33

being proved wrong. I have always

1:20:35

believed that the reason we

1:20:37

saw an increase in fasting

1:20:39

lactate, even in healthy people,

1:20:41

if they took Metformin

1:20:43

was because of the inhibition

1:20:45

of the ECT in skeletal

1:20:47

muscle. And you're saying Peter,

1:20:49

that's not possible, it can't

1:20:51

get into skeletal muscle? Absolutely,

1:20:53

not a single molecule in

1:20:55

the world of metformin has

1:20:57

ever gotten into any skeletal

1:21:00

muscle anywhere. And tell me

1:21:02

again why, what's the transporter?

1:21:04

The organic cation transporter. That's

1:21:06

the transporter by which metformin

1:21:08

enters cells. It does not

1:21:10

exist in skeletal muscle. It

1:21:12

does not exist in cardiac

1:21:14

muscle. So metformin cannot

1:21:16

get into these tissues. It's

1:21:18

a huge major

1:21:20

misconception. It can, if

1:21:22

you have very, very high doses, that

1:21:24

can occur when you have very low

1:21:27

GFR. Because metformin is excreted

1:21:29

by the kidney. If the metformin

1:21:31

levels build up, you can get

1:21:33

lactic acid doses. That's a very, very

1:21:35

rare complication. That's not a reason

1:21:37

why you shouldn't be using the metformin.

1:21:39

And I'm not saying that metformin

1:21:41

is not a good drug. It is

1:21:43

a good drug. I don't think

1:21:45

it's as good as the other three

1:21:47

drugs we talked about, but yes,

1:21:49

it does add high doses, increase the

1:21:51

lactate level, all in effect on

1:21:53

the liver. And the old drug that

1:21:55

caused all the problem was fendformin

1:21:57

by guanide as well, but it had

1:21:59

a powerful effect. Yeah, fendformin was

1:22:01

much more powerful. Yes. And when you

1:22:03

say high dose, I mean, is

1:22:05

two grams a day of metformin? No,

1:22:07

no, no, no. That's the normal

1:22:09

dose. That's the normal dose. Okay, so

1:22:11

metformin has the following going for

1:22:13

it. It's free. Yes, it's basically free.

1:22:16

Yeah, it's free. Absolutely. And it

1:22:18

does a pretty good job at reducing

1:22:20

hepatic glucose output. Yeah. And it

1:22:22

has no myotoxicity, frankly, any toxicity. GI.

1:22:24

Yeah, the GI, but you can usually overcome

1:22:26

that with a slow ramp up. Yeah. See, this

1:22:28

is the reason why some people thought it's

1:22:30

an insulin sensitizer. 15 to 20

1:22:32

% of people have significant GI

1:22:34

side effects and they lose weight.

1:22:36

And if you look at the

1:22:38

studies, On average, there's about a

1:22:40

three kilogram weight loss with metformin.

1:22:42

And when you lose weight, you

1:22:44

can improve insulin sensitivity. So

1:22:47

I think this is what's confused

1:22:49

some of the old literature to

1:22:51

make people think that metformin was

1:22:53

an insulin sensitizer. But when we

1:22:55

developed metformin, and I did all

1:22:57

of the work that went to

1:22:59

the FDA, if you look at

1:23:01

the New England Journal of Medicine,

1:23:03

article 19C95, there are only two

1:23:05

names on the paper. Myself and...

1:23:07

PhD oncology lady who was the

1:23:10

person from leaf and pharmaceuticals. We

1:23:12

did insulin clamps, many of them.

1:23:14

We never could show me a

1:23:16

form of an improved insulin sensitivity

1:23:18

using the gold standard with radioisotopes.

1:23:20

Do you think many people, I

1:23:22

feel like I'm asking you this question

1:23:24

a lot and it's getting a little old,

1:23:26

but do you get the sense that

1:23:29

most people are still thinking what I think?

1:23:31

Yes. Metformin gets into the muscle. Yes.

1:23:33

Metformin is an insulin sensitizer. Absolutely. And it's

1:23:35

an insulin sensitizer by getting into the

1:23:37

muscle and inhibiting complex one. Absolutely. People have

1:23:39

done PET studies, so you can label

1:23:41

metformin and you give it. And then where

1:23:43

do you see? It's all accumulating in

1:23:45

the liver in the first three, four, five,

1:23:47

ten minutes. And then what happens? You

1:23:49

start to see it accumulating in the kidney.

1:23:52

Why? Because that's where it's excreted. And then wait another

1:23:54

five or ten minutes, you see in the bladder. And

1:23:57

that's the only place where you see Metformin,

1:23:59

you never see it in the muscle.

1:24:01

And that's even more graphic demonstration

1:24:03

that metformin is not getting in the

1:24:05

muscle. And it is definitely not

1:24:07

an insulin sensitizer. Is there a downside

1:24:09

to using metformin in combination with

1:24:11

the other three drugs? No. The classic

1:24:14

study which we'll talk about, which

1:24:16

to me should change the entire approach

1:24:18

to treating diabetes, is called the

1:24:20

edict study. And in the

1:24:22

edict study, what we did is

1:24:24

we used triple therapy right from

1:24:26

the beginning. And my point

1:24:28

of the banting lecture, the

1:24:30

ominous octet, if you have eight

1:24:32

problems, I'm sure going to be more

1:24:35

to be found than I can give you a few

1:24:37

more if you want. But if you have eight problems, why

1:24:39

in the world do you think one drug is going

1:24:41

to correct eight problems? It ain't going to happen in our

1:24:43

lifetime. So the point was you

1:24:45

need to use drugs in combination. We

1:24:47

said we're going to use what we

1:24:49

think are the best drugs at the time.

1:24:52

So we started with metformin. with Exenotide, an

1:24:55

old -time GLP1. And this is not

1:24:57

the kingpin. This is the pre -Liraglutide.

1:24:59

Yeah, exactly. Because that's what was

1:25:01

available. That drug was useless, wasn't it?

1:25:03

No, it's a good drug. Sure,

1:25:05

it's not Semaglutide. But you have to

1:25:07

start somewhere, right? Yeah. Let's pay

1:25:09

it its dues as being the Gen

1:25:11

1 OG version of that drug.

1:25:13

Without which we might not have... We

1:25:15

wouldn't have Semaglutide or Tisepetide. Yes.

1:25:17

It's kind of an old -timer in

1:25:19

Peoglutisone. That was the triple therapy. And

1:25:21

then we said, every diabetic patient.

1:25:23

There are 315 people in the study.

1:25:26

They're having insulin clamps, hyperglycemic clamps, muscle

1:25:28

bibes. No one in the world

1:25:30

can do this study. 315 people. Followed

1:25:32

for six years. So we said,

1:25:34

this is what we believe is the

1:25:37

appropriate therapy. Then we said, we'll

1:25:39

use the ADA approach. The ADA

1:25:41

approach is you start a metformin.

1:25:43

And when you fail, even not

1:25:45

explicitly said, the next drug that's

1:25:47

used is cell phone ureas. And

1:25:49

then the third drug that's added

1:25:51

is insulin. And we said that

1:25:53

the goal of therapy was an

1:25:55

A1C of six and a half,

1:25:57

okay? And that if your A1C

1:25:59

rose above six and a half,

1:26:02

either on our triple therapy or

1:26:04

on the stepwise treat -to -fail approach

1:26:06

that the ADA says. ADA says,

1:26:08

start metformin, you fail, you add

1:26:10

sulfonylurea, you fail, you add insulin,

1:26:12

you titrate the insulin basal insulin

1:26:14

up to 60 units. And we

1:26:16

said 60 units is really, we'll

1:26:18

cap it. Yeah, you're already at

1:26:20

2x physiologic. Yep. Now you have

1:26:22

to split the dose of insulin.

1:26:25

You have to be adding rapid

1:26:27

acting insulin. I think this is

1:26:29

quite reasonable. Six years later, 29

1:26:31

% of the people with the

1:26:33

ADA approach have failed. Their

1:26:36

A1C is above six and a

1:26:38

half. Six years later, with

1:26:40

our approach, 70 % of the

1:26:42

people have an A1C. It's less

1:26:44

than six and a half. Why? Insulin

1:26:47

clamp. Huge improvement with our therapy.

1:26:49

Okay, this the EDIC study. The three

1:26:51

-year data published, the six -year data

1:26:53

we're writing it up. How much improvement

1:26:55

in insulin sensitivity with the ADA

1:26:57

approach? Zero. Beta cell function, you

1:26:59

have almost a normal beta cell. Ralph, why

1:27:01

the disconnect between what you're seeing in the

1:27:03

EDIC study and what the ADA is promoting? You

1:27:06

have to ask the ADA. What's

1:27:08

their answer? If I'm a patient or if

1:27:10

I'm a physician who's treating these patients

1:27:12

and I'm saying, guys, I'm confused, I'm looking

1:27:14

at the literature, I'm seeing this, I'm

1:27:16

looking at your... And by the way, I

1:27:18

see this with the AHA and cardiovascular

1:27:21

guidance, so I'm not singling out U, but

1:27:23

is this simply a question of the

1:27:25

pace at which medicine moves is so glacial?

1:27:27

That's part of it. Plus, remember,

1:27:29

if to do 315 people, follow

1:27:31

them for 16 years and do

1:27:33

all the stuff we did, it's

1:27:35

unequivocal. And why has there not

1:27:37

been political pressure? Because the cost

1:27:39

of insulin is enormous. Your approach

1:27:41

is going to be less expensive.

1:27:44

They finally said in 2022, there's

1:27:46

a state. The ADA approach is

1:27:48

not based on pathophysiology. I view

1:27:50

myself as a scientist, as well

1:27:52

as a clinician. As a

1:27:54

good clinician, I take care of

1:27:56

hundreds of thousands of patients and at

1:27:59

850 publications. I do

1:28:01

clinical research. I work in people. When

1:28:03

I do an insulin clamp study and

1:28:05

I see an improvement in insulin sensitivity, I

1:28:07

do a hyperglycemic clamp. And I

1:28:09

see in 315 people, your beta cell

1:28:11

function, I don't need 5 ,000 people.

1:28:13

I can't do this study in

1:28:15

5 ,000 people. No one can do

1:28:17

this study. But the tools that we're

1:28:19

using are so powerful. Look,

1:28:22

if I normalize your insulin sensitivity, and

1:28:24

I give you a normal beta cell,

1:28:26

and your A1C is less than six

1:28:28

and a half, well, it's half of

1:28:30

the 315 people, why you not think

1:28:32

that's the best therapy? And now on

1:28:34

the other side, I have this metformin

1:28:36

SU insulin. and 71 % of the people

1:28:38

have failed, there's zero improvement in insulin

1:28:41

sensitivity, zero improvement in beta cell function,

1:28:43

while you think that's such a good

1:28:45

regimen. Now, above and beyond all

1:28:47

that, I didn't do this study. This

1:28:49

is the great study, G -R

1:28:51

-A -D -E. It's sponsored by

1:28:54

the National Institutes of Health. And

1:28:56

what the great study said, and

1:28:58

I have to say this is the

1:29:00

third study that's shown what I'm going

1:29:02

to tell you. Dr. Robert Turner's United

1:29:04

Kingdom Prospective Diabetes Studies showed this in

1:29:07

1990. Stephen Kahn showed this

1:29:09

in the Adopt Study in year 2005.

1:29:11

And now we have the Great Study,

1:29:13

2020. I call this the 15

1:29:15

year revelation. We saw what didn't work

1:29:18

1990. Oh, Stephen Kahn

1:29:20

did it again. Oh, it didn't

1:29:22

work in 2005. And now 2020,

1:29:25

NIH did it. You know what? I'll show

1:29:27

the same thing. And this was a sequential

1:29:29

approach. You had to have failed on metformin

1:29:31

to get into the study. Okay, so you

1:29:33

failed in metformin, then you enter the study,

1:29:35

then we go single agent. They wanted to

1:29:37

know what's the best next drug to add

1:29:39

to metformin. I can add a

1:29:41

sulfonylurea, A1C went down in year

1:29:43

one, up straight. Tell folks how

1:29:45

a sulfonylurea works. Sulfonylureas

1:29:47

are old time drugs. They bind to

1:29:50

the sulfonylurea receptor on the beta cell

1:29:52

and they kick out insulin. And

1:29:54

they're very good drugs in the first

1:29:56

year. And then they burn out the pancreas.

1:29:58

Well, they stop working. Yeah. I mean,

1:30:00

basically, they kick the can down the road

1:30:02

without addressing the pathophysiology. I like that

1:30:04

way. Other drug, DPP4 inhibitor.

1:30:06

Tell people how those work. Yep.

1:30:08

So a DPP4 inhibitor increases your

1:30:10

GLP1 and your GIP level endogenously.

1:30:12

It makes your gastrointestinal cells, the

1:30:14

K and the L cells, that

1:30:16

secrete the GLP1 and GIP, makes

1:30:19

them make more GLP1 and GIP.

1:30:21

But it doesn't increase the GLP1

1:30:23

and GIP. enough to really give

1:30:25

you a knockout punch. I give

1:30:27

you an injection, you all, people

1:30:29

are out there, Monjaro or Semaglutide,

1:30:31

that's the knockout punch. When I

1:30:33

give you the DPP4 inhibitors, they

1:30:35

do increase GLP1 and GIP a

1:30:38

little bit, but not powerful enough

1:30:40

to give you a long lasting

1:30:42

effect. So, first year, A1C comes

1:30:44

down, shh, A1C goes up. Third

1:30:46

drug, this was very surprising to

1:30:48

me. This was Lyriglutide. This is

1:30:50

one of the earlier GLP1 receptor

1:30:52

agonists. I thought that was going

1:30:54

to work. the best. It

1:30:56

failed. It worked in the first year and

1:30:59

then failed. And then the

1:31:01

fourth drug was insulin. And the

1:31:03

docs just didn't titrate the insulin

1:31:05

enough, so they went see it out

1:31:07