Lessons from the Human Pancreas: Rewriting the Textbooks on How Type 1 Diabetes Develops

November 11, 2021

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November 4, 2021

Yale Pathology Grand Rounds

Mark A. Atkinson, PhD

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00:04First, the uh, you know, do you
00:06know the introduction perfect?
00:11OK, we'll start a good afternoon everyone.
00:15Welcome to pathology grand rounds,
00:19so it is really my great pleasure and
00:21a privilege to introduce you today.
00:24Speaker Doctor Mark Atkinson
00:26from the University of Florida.
00:29So doctor I concern is a
00:31really a world renowned type.
00:32One diabetic diabetic investigator,
00:35an outstanding teacher and a mentor,
00:38an end a prominent.
00:41Leader in the scientific community.
00:43So he has a really long
00:45and very impressive CV,
00:47and it will take the whole hour to
00:49talk about the marks achievement
00:51over the past 30 decades.
00:53So I decided just to you know,
00:56to do a brief introduction,
00:58introduction to mark.
00:59So I had the privilege,
01:02privilege and opportunity to work with
01:05Mark in the Department of Pathology
01:08at the US will almost 16 years.
01:11So I think I really know a lot about him.
01:14Mark so Mark is currently the American
01:19Diabetes Association eminent scholar for
01:22diabetic Research and Jeffrey Kinney,
01:25family professor at the
01:28Department of Pathology,
01:29Immunology and Laboratory Medicine at EU.
01:32F.
01:32He he is the founding director
01:36of the Diabetes Institute at UF.
01:39Market received his bachelor's degree
01:41from University of Michigan and
01:44his PhD Tigre at the University of
01:47Florida and then stated there things.
01:51A Marca has been working on
01:54diabetic type one diabetes.
01:56For most, I believe is almost 40 years right?
01:58Correct me if I'm wrong, if I'm wrong.
02:01So he has published nearly 600
02:03papers and I I know several of his
02:06papers are among the most quoted
02:08paper in the field of diabetes.
02:11So he hasn't received the most
02:13and 75 million grants,
02:14and he's always well, Ralph,
02:16well funded from multiple sources.
02:19That certainly is the, you know,
02:21an age and he has holding
02:23this type one diabetes pill,
02:25one for long period of time.
02:28Mark has been the recipient
02:31recipients of multiple scientific
02:33and humanitarian based wars.
02:36I will just mention a few here.
02:39He received a Gerald Gala,
02:42Grosky award,
02:43Mary Tyler Moore and Robert Levin
02:47Award from juvenile Diabetes Research
02:50Foundation the he's also called.
02:54He received a prestigious Eli
02:57Lilly Award for Understanding
02:59scientific achievement from
03:01American Diabetes Association,
03:04also called JDA.
03:06He received that they hire strong
03:09award from Sweden and recently
03:11he received the UF College of
03:15Medicine Lifetime Achievement Award.
03:18And he also received the Jacob Jacobo
03:21Award from the Nova Nordisk Foundation,
03:25really the most prestigious international
03:28award in endocrinology and Metabolism.
03:32Besides his scientific achievement,
03:34mark has also actively engaged in
03:38leadership services to type one
03:41diabetes community with active
03:44administrative or advisory services to JDRF,
03:47the American Diabetic Association,
03:50the National Institute of Health,
03:52at the Immunology of Diabetes,
03:55Society,
03:55and various variety of companies from
03:59pharmaceutical and about industry.
04:01And I would particularly like to
04:04highlight the two great programs
04:07that Mark funded from scratch,
04:09and I had the opportunity to
04:12actually witness myself.
04:14One is the JDRF network for pancreatic
04:18organ donate donors with diabetes.
04:21The acronym is Empire,
04:23which you will hear from Mark
04:26today. I would say it is epic example
04:30of how tissue repository can make.
04:33Impact on scientific discovery.
04:35The end part is now supporting
04:37more than 300 research projects.
04:40Over 200 / 24 countries.
04:42The other program is that he founded the
04:45university level Diabetic Institute at USC.
04:49So Mark are all also serves in many
04:52scientific organization editorial,
04:54board of journals,
04:55and the charitable foundations.
04:57I just highlighted one particular one.
04:59I think it's really remarkable.
05:01So Mark is now the president
05:03of insulin for life.
05:04USA, the world's second largest charity,
05:08dedicated to providing insulin to people
05:11living with diabetes in the developing world.
05:14I will say without further ado,
05:16I now turn it to mark for his lecture
05:20titled license from the Human Pancreas,
05:23rewriting the textbooks and
05:25how type one diabetes develop.
05:27Mark is yours.
05:28Thank you.
05:29Again,
05:30thank you for visiting Yale
05:33chanting. Thank you very much for
05:36that warm introduction and you can
05:38write my eulogy one day if you want.
05:41Won't be for awhile, but anyway,
05:43that was very kind of you and I to
05:46everybody at Yale like I wish I were
05:48up there in person to present this,
05:50but we will try and make it
05:53through as good as we can today.
05:55So thank you again and what I
05:58wanted to do is kind of build on
06:00what Ken said is to try and show
06:03some lessons on how studies of the
06:05tissues can really contribute to an
06:08improved understanding of disease.
06:10And I think in the case.
06:12So then pod,
06:13the effort that Chen introduced below.
06:16That's a we we really are doing that in
06:19terms of updating our understanding so.
06:24Yeah, again, just keeping with CMA,
06:27he notions these are some of the companies
06:29that I worked with over the past five years,
06:32but nothing today will discuss will relate
06:35to any of their activities or drugs so.
06:40Wanna add like like one of the
06:43things that in that goes with type
06:46one diabetes research is when you,
06:48especially when you speak to
06:50groups of lay individuals.
06:51People say well,
06:52when is type one diabetes
06:54is going to be cured.
06:55And part of this is driven because in them.
06:59So either social media or
07:01old-fashioned newspapers.
07:02There's just constantly been essentially
07:04almost in my whole career news reports
07:07that the cure of type one diabetes
07:09is around the corner or three to
07:11five years away is a common thing,
07:14and it's been one of the biggest challenges
07:18is to try and convince people that
07:22you know we're trying to do this and.
07:26Try and take on this challenge
07:28of what they see in the media,
07:31but this is not a new event and
07:33that actually this year marks the
07:36100th anniversary of the ability
07:38to isolate insulin,
07:39which back again 100 years ago,
07:42was a Nobel Prize winning event.
07:44But this newspaper headline from
07:46the Toronto Daily Star back then.
07:49It even says the doctors on track of the
07:53cure for diabetes didn't quite turn out that.
07:56Wait, but uhm,
07:57it's it's been 100 years of
08:00trials to try and do that.
08:03And then the reason I put this slide
08:05in here and it's a couple of years.
08:07Old now is certainly not been
08:10for lack of trying.
08:13At this time on this Lancet
08:14article that we put together,
08:15we just looked back in the previous
08:18decade of attempts to try and intervene
08:20in terms of type one diabetes.
08:23This just being on the immune
08:25mediated trials.
08:26This did not include things like.
08:30The antigen,
08:31specific therapies and the like,
08:33but just targeting the immune system
08:35and in many different ways and so
08:38at that time they were about 52
08:40completed trials and 25 that we
08:43recruit recruiting and we're still
08:44in that situation today in many
08:46ways and that there are trials
08:48going on both in the
08:49United States and Europe.
08:50All that they're attempting to do.
08:52Usually one of two things,
08:54either delay the prevention
08:57of onset of the disease so.
09:00If you have individuals that are high risk,
09:03try and keep them from developing.
09:06The need for exogenous insulin therapy,
09:09but then or the other thing is,
09:11is if you're diagnosed with the disease
09:13to try and again continue to have
09:16the person produce insulin in the
09:18OR we what we measure in C peptide.
09:21So a lot of attempts to try and do this.
09:23But as of today we we don't
09:25have such a therapy that's been
09:28approved by regulatory agencies,
09:30although thanks to one of your own doctor
09:33Harold and others in the Community,
09:35we we feel like.
09:37We're closer than ever,
09:38but one of the reasons so I wanted to
09:41set this up in this first five minutes.
09:43Why haven't we been able to cure the disease?
09:46And I think there's a number of
09:48reasons to that underlie this,
09:50and one is,
09:51is that we still have knowledge voids in
09:54terms of how exactly the disease developed,
09:57and this is not meant to
09:59be a sarcastic slide.
10:00But what I did was I went back
10:02and found like major articles
10:04that were published back in 1992.
10:06Number of years later,
10:082007,
10:09and then even last year and you can see
10:12that actually all the way back to 1992.
10:16That they said that you know there's
10:18these B cells that make antibody.
10:20There's the beta cells,
10:22the cells that are destroyed there's an
10:26antigen presenting cell involved in.
10:29What I I guess the point I'm trying
10:30to make here is that the key
10:32and core elements really haven't
10:34changed that much overtime.
10:35I I'm not mocking the field,
10:37there are where we certainly have
10:39a lot more complexity than this,
10:40but we still are faced with a situation
10:43where we really don't know how Type
10:461 develops and when that occurs it
10:48you're forced into situations like
10:50the previous slide where you have
10:53to try a lot of different things.
10:55In order to try and see,
10:56find something that perhaps made success.
10:59That's just one thing,
11:00and that if you were to pull.
11:04100 different type one diabetes
11:06investigators and say,
11:07why do you think we haven't cured it?
11:09Everybody would have their own list
11:11and I'm not going to go through
11:13all of these for the sake of time,
11:15but I'm going to just highlight the last two.
11:18This would be my list and I think
11:21one of them has been the influence of
11:23dogma in the field over the years.
11:25Meaning there there were a number of
11:27assumptions or that people thought.
11:30Well, this is true about type one diabetes
11:32and there weren't a whole lot of challenges.
11:34To them, in all cases and the other thing,
11:37and this is maybe good for this audience.
11:40In particular, I think we had a lack
11:42of understanding pancreatic pathology,
11:45or there there has been up until date.
11:48And so let's start out there talking about
11:51some of those dogmas that are out there.
11:53And I think if you were to actually
11:56take the literature on type one
11:59diabetes almost in its pathogenesis,
12:02it's Natural History.
12:03Almost every.
12:05Article the first sentence,
12:07if not the first sentence,
12:08the second sentence is this up at the
12:11top that type one diabetes results
12:13from an autoimmune T cell mediated
12:15destruction of the pancreatic beta cells.
12:18This this is a central document for disease
12:21and everybody puts it out there and there.
12:23There's good reason for it,
12:25if that we've known for well over
12:27100 years that the pancreas of type
12:29one diabetes has this insulitis.
12:31So if you remember that in the
12:33pancreas about 1 to 2% of that organ.
12:36Is made up of these insulin,
12:38producing another hormone,
12:40producing islet cells,
12:41and they do have a a limp acidic
12:45infiltration associated with it.
12:46We know that in terms of genetic
12:49susceptibility and the the major genes
12:52forming type one diabetes are associated
12:54with the major compatibility complex.
12:57So right central to immune responsiveness
13:00and then the third thing is,
13:01is the presence of autoantibodies that
13:04we've known again since the mid 70s?
13:07Their patients with the disease
13:09develop antibodies that react with
13:11different constituents of of the island,
13:14and you could if you do immuno indirect
13:17immunofluorescence tests you can see them.
13:19The other, the second probably most
13:21touted dogma of type one diabetes,
13:24is this Natural History model,
13:26and it was put together.
13:27By one of my best friends and
13:31mentors in life,
13:32George Eisenbarth,
13:33he published this back in the mid 80s.
13:36This model for the disease and
13:39unfortunately George passed
13:40in 2012 of pancreatic cancer.
13:42But this this has been the central road
13:46map since the mid 1980s for almost all
13:49of human type one diabetes research.
13:51When you talk about the Natural
13:54History of the disease and the
13:56challenge we have and will will.
13:57Re address this at the end is is
14:00that I'm unfortunately and George
14:01would have if he were still alive.
14:03He would admit this to the day
14:06this is served as an exceptional
14:08road map for the disease,
14:10but so many components of it
14:13are not quite right.
14:15But and they they needed to update it.
14:18But it's again.
14:19It's been a dogma so few few
14:21people have questioned it.
14:23And so I thought again, just in the
14:26closing down the introduction here,
14:27I'm going to give you some.
14:28Examples of the dogma that have
14:30existed in terms of type 1 diabetes.
14:32But now thanks to pathology,
14:34I'll show later.
14:35You'll see that they're not all exactly true.
14:39So one of the realities is that as
14:42the individuals throughout the United
14:45States and actually globally today,
14:47if they're diagnosed with type
14:49one diabetes on most occasions,
14:50they're going to be told that the
14:53reason that you're here today is
14:56because of this autoimmune destruction
14:58and somewhere around 85 to 90% of
15:00your beta cells have been destroyed.
15:02Well, now through studies of the pancreas,
15:04we now know that actually you
15:06can have as little as a 50%
15:08loss of functional beta cells.
15:10And about disease,
15:11and in some cases it is quite
15:13high in terms of percentage,
15:15but it actually varies from person to
15:18person and will explain some of that later.
15:21But this is a dogma that
15:23people just keep getting told.
15:24Another thing is, is that and I,
15:28I think pathology is bearing this out.
15:31This is that we pretty much
15:32worked as type one, diabetes,
15:33being a singular disease,
15:35and it's true that in type one diabetes
15:38people become insulin requiring.
15:40But in the reality is is you can
15:42develop this disease as a one year old,
15:44a 10 year old,
15:45a 30 year old,
15:46a 60 year old individual and
15:48we now know through studies.
15:50Like I said a pathology genetics,
15:52the immune response that there's
15:54differences that seem to be aligning here
15:57that it may be that type one diabetes
16:00is more of a syndrome of disorders
16:02with different pathogenic processes
16:05leading to this insulin requirement.
16:08Another thing is is that for almost my
16:12total career here is is that it was there.
16:15Was this clear separation between
16:17what's type one diabetes versus type
16:202 diabetes and that type one type 2
16:24diabetes was a disease of obesity.
16:26And had different genetics and and the
16:29pathogenic mechanisms were quite different.
16:31The reality is is now that
16:32we go to the pancreas,
16:33although they're still limited.
16:36There are some commonalities that
16:38we're beginning to see between
16:41type one and type 2 diabetes,
16:43and another thing that's partially
16:45supportive of this is is that we're
16:48actually now seeing a situation
16:49where drugs created for type 2
16:51diabetes are being utilized in
16:53settings of type one diabetes and so.
16:56I think there's a little bit more Gray here,
16:58but historically these have
17:00been siloed as disorders,
17:02but these are documents,
17:03So what what's led to some of the
17:06changes in the dogmas and why?
17:08Why am I here today promoting pathology?
17:11Actually,
17:11it's some of the greatest discoveries
17:13we've had in the field of diabetes.
17:16Have come through studies
17:18of pathology by pathologists
17:21and I just put some examples here.
17:23On the left. We call them islet
17:25of langerhan's because of that,
17:27that Discovery Schmidt on the right and
17:30German pathologist was the one that
17:32first discovered the infiltrate and then
17:34we've had individuals that notice that
17:36some people with diabetes had this.
17:39Infiltrate other ones didn't.
17:41But with the decline of autopsies
17:44in the 1960s and over the years,
17:47improvements in diabetes management at onset.
17:51The studies of the human pancreas
17:52kind of fell out of favor and another
17:55reason is because of the availability
17:57of mouse models of the disease.
17:59So back in the early to the mid 2000s,
18:03George had an idea and met with
18:05me and we talked about.
18:08Could we use organ donors to try and
18:10study the pathology of the human pancreas?
18:12Not going into all the details
18:14on how that happened,
18:15but we ended up as Ken said,
18:18forming this network called N Pod
18:20for the network for pancreatic
18:22organ donors with diabetes.
18:25And the goal here was pretty simple was
18:27to try and obtain pancreas and other tissues.
18:31Transplant quality tissues,
18:33not autopsy tissues,
18:34from individuals with the goal of
18:37trying to better understand how and
18:40why type one diabetes develops.
18:42And so this is an example of a
18:45screenshot I took a couple days
18:47ago in that in just referred to.
18:49So what we do is collect transplant grade
18:51tissues and they're they're listed there.
18:54We operate 24/7 365 UM we we've
18:58collected actually almost 1000 organ
19:01donors with all of our program,
19:03but those related to impound
19:06or some almost 600 number now.
19:08And again,
19:09you can see we collect them from controls,
19:11which is very important to us to
19:13understand what controls are and
19:15then individuals with type one
19:16diabetes or this very informative
19:18group called auto antibody positive.
19:20So these are individuals that
19:22are increased risk for diabetes
19:24but actually have not developed
19:26the symptoms of the disease.
19:28And then we collect diabetes and a
19:30number of other forms to to kind
19:33of round out the the analysis.
19:37So what what I want to talk today and
19:39over the next few minutes is what did
19:41we learn from studies of the tissues.
19:43So the first lesson we've learned is,
19:45and I I would say,
19:46we've affirmed.
19:47It is that type one diabetes is an
19:49autoimmune disorder with immune
19:51infiltration of the pancreatic islets,
19:53as shown here or again, red.
19:56The red stain represents insulin,
19:59and then the brown,
20:01the lymphocytic infiltration.
20:02Well,
20:03one of the first things that we re
20:07noticed if you would was is that
20:10the type of insulitis you see in
20:12our mouse models is very very
20:15different from as a whole.
20:17With that in the human disease
20:20and we've even noticed overtime
20:23that it's quantitatively.
20:25Qualitatively and quantitatively different.
20:26So if you look at the mouse model on
20:29the left, often we it's in stages.
20:32It's almost like staging cancer,
20:35or that where you have the grades,
20:39whereas in the humans it's more just
20:41what we say is it present or absent.
20:47And we actually a few years ago now
20:50brought together pathologists from around
20:52the world that had and we met in in
20:55Cambridge and tried to come up with a
20:58universal definition of what insulitis is.
21:00And what we the we are consensus
21:03definition of INSULITIS was is that
21:06you had to have within a given case 3
21:09islets with 15 white blood cells present.
21:13And then we would say that that
21:15case had insulitis.
21:16If we went very much off of that,
21:19we would be, we would have a lot of cases of
21:22type one diabetes that didn't have insulitis.
21:25Another thing that and I'll show
21:27example of this is we said there
21:29needed to be pseudo atrophic.
21:30Pilots within this section, meaning islets
21:33devoid of the insulin producing cells.
21:36But this is very different
21:38from the NOD's as a whole,
21:40although exceptions do exist,
21:41it's just much more common in NOD.
21:45Now, in terms of the type
21:47of of cells that infiltrate,
21:50it's pretty much a catch catch.
21:51Can there's B cells, T cells,
21:55CD4 CD, 8 macrophages,
21:58dendritic cells,
21:59but in humans the most predominant
22:03one is the CD8T cell.
22:05But another dogma that we
22:07were able to bust was.
22:10There there were thoughts that actually
22:12mostly insulitis would occur at or
22:15around the onset of type one diabetes,
22:17and that within a few months to
22:20a couple years of disease onset,
22:22that with the losses of beta
22:24cells that it would go away.
22:25And actually through studies of
22:27long term patients we can act.
22:30We've actually shown that it
22:32insulitis can exist for many,
22:34many,
22:34many years after the onset of
22:37symptomatic onset of disease,
22:38as can the presence of.
22:40Insulin positive cells.
22:44And this is an example of this is
22:46actually the first time I've ever
22:48shown this publicly to an audience.
22:49We've developed a new technique
22:51where we can take live tissue slices.
22:53These are about 125 Micron thick
22:56sections stained them,
22:58so this is within hours.
22:59They have actually case recovery and we do.
23:03This is like a 30 minute video
23:06collapse down to 88 seconds,
23:08but those magenta colored cells are
23:11stained T cells that are stained.
23:15And the.
23:16Autofluorescence in white and
23:17the yellow is a viability dye,
23:20but this just again shows
23:22the autoreactivity here.
23:23In this patient I should have said
23:25that this is from a patient that
23:27about two weeks ago that unfortunately
23:30expired right at the onset of type
23:33one diabetes or at the diagnosis
23:35they were about 20 years of age,
23:37had autoantibodies but died in onset.
23:40So we are that again.
23:44We believe shows proof of the auto.
23:47Community being important than disease.
23:50Another facet that we know supports
23:53the autoimmune nature of the
23:55disease has to do with an article
23:57we and Sally can't publish,
23:59and a number of others published
24:01in Nature Medicine a few years ago
24:03now where we actually took tissue
24:05samples like those I just showed
24:07you grew out the T cells or from
24:10him and then asked what
24:11they were responding to
24:13and the good news here is,
24:15is that a number of the.
24:17Targets that are listed there,
24:18like Gadai 2 and insulin.
24:21These are targets of autoantibodies
24:23that for years we've been measuring in
24:26peripheral blood in serum and plasma,
24:29so this was very.
24:30Informative to us because it
24:32told us that we were kind of
24:34on the right trail in terms of
24:36understanding the autoantigens
24:37responsible for type one diabetes.
24:41Now another thing that will that touts
24:43this notion of disease heterogeneity
24:45or subgroups of type one diabetes
24:48came from more pathology based
24:50studies that first started with a
24:53historical collection in Europe and
24:56then now have moved on to end pot.
24:59So I'll just break it up here
25:00on the left hand side.
25:02I'm only going to focus on it is if
25:04you look at the B cell population
25:06that are high expresser's of CD 20.
25:09If you're diagnosed with the disease.
25:12Less than 15 years of age,
25:14you tend to have a high percentage of
25:16B lymphocytes in that infiltrate that.
25:18I showed you the insulitis lesion,
25:20but if you're diagnosed with type
25:23one diabetes above 15 years of age,
25:25the frequency of those CD 20 cells and
25:29their intensity is much, much less.
25:32Switch again starts to tell us that
25:35there may be different pathogenic
25:37mechanisms based on the age of onset.
25:40Another thing,
25:41and it's kind of interesting that
25:44early on we started noticing this
25:46phenomenon in in the tissue samples
25:48from in pot in George views that in
25:51a a major lecture that was given at
25:54the American Diabetes Association
25:56meeting was is that the loss of insulin
25:59secreting cells was quite lobular in nature,
26:01and if you look and he called
26:04it the vitiligo of the pancreas,
26:06meaning if you if you everybody
26:08here on this call will know about
26:10the deep pigmentation that.
26:11Occurs in bilago as shown
26:13on the right hand side.
26:15What we have is you'll have lobules
26:17where the pink is the insulin staining,
26:21and but then they'll be right
26:23adjacent to lobules where there
26:25won't be any insulin staining.
26:26Now if we were to do other counter
26:28stains for other island hormones
26:29you would see there I'll it's there,
26:31but the the loss of islets is quite patchy,
26:36hence why we this called little I go.
26:38Now we're not sure exactly why some I
26:41let's get destroyed and others don't,
26:44but we have some clues,
26:46and one of them is what we call the
26:49hyper expression of class one MHC,
26:51and I give some examples across the
26:53top of what a normal in an island of
26:56what a normal classroom would look like,
26:58elevated,
26:59or what we call hyper expression.
27:01And then there's a A on the right hand side,
27:05shows three different groups.
27:07One is the controls.
27:09And what there the MFA for the
27:11expression of class one is like?
27:13And then the other one is type
27:15one diabetes and I see I means
27:17insulin containing islands.
27:18So if you have insulin and you have
27:20type one diabetes, those islands seem
27:22to have a lot of Class 1, whereas if
27:24you go in insulin deficient islets,
27:27which is the far right column, no insulin.
27:30Their their level of class one is is
27:33more much more like control tissues.
27:35So one of the things we feel
27:37like May distinguish in islet.
27:39That's going to be destroyed versus
27:41one that isn't has to do with this.
27:43Class one MHC,
27:44which may be more like a danger response.
27:48So we have a clear view that type one
27:51diabetes is an autoimmune disease.
27:53But now with the the each next
27:56lesson that I'm going to give him,
27:58there's four in total.
27:59Is is that we also now believe that
28:01type one diabetes is a disease
28:04of islets and beta cells.
28:05And that let me go.
28:06Why say that?
28:08So again, if you,
28:09if you take a look at the type one pancreas,
28:12what you'll see the?
28:13Depending on the degree of duration,
28:16disease, duration,
28:17you'll see varying amounts of these.
28:19What we again called pseudo atrophic islets.
28:22These ones in the middle,
28:22where they'll be hormone island hormone
28:25positive but deficient of insulin staining.
28:29And then there will be other
28:31types of violence like the one on
28:33the right which will be insulin
28:34positive islet with insulitis.
28:36And then they're all even be one
28:37like on the left where you have
28:39it in an insulin positive islet,
28:40but without insolitus.
28:42So you end up with this mosaic of of
28:45different types of islets in there.
28:47But why is one destroyed?
28:50And why is not?
28:51And are they really like on the
28:53left hand side?
28:54Are they really normal and so?
28:57The answer is no.
28:58And I'm going to go through these next
29:01slides very quickly for the sake of time,
29:03but one of the things that impot
29:05investigators have found out is,
29:07is that if you look at expression
29:10markers of stress responses that there
29:13are footprints of stress responses.
29:15They're very much elevated in
29:18the type one diabetes pancreas.
29:21Another thing is that if you
29:23start to take a look at certain
29:25processes within the islets of
29:27somebody with type one diabetes,
29:29things like this is a science
29:31translational medicine paper.
29:33The unfolded protein response is abnormal
29:35in the type one diabetic eye lid,
29:38so it doesn't process normal as normal.
29:42Another thing,
29:43and this is big in the
29:44cancer field that you know,
29:45Senate markers of senescence
29:48essentially aging.
29:49If you take a look at aging markers
29:52in the in the island of a non
29:55diabetic shown on the left hand side.
29:57So P21P16 if you look at the
30:00auto antibody positive pancreas.
30:01So again these are don't have
30:04diabetes yet but are at risk for
30:07disease or the type one diabetic
30:09on the right and quantitate it.
30:11Type one and at risk people have far
30:14higher levels of senescent cells,
30:17senescent beta cells than
30:19control individuals,
30:20suggesting almost like a premature aging.
30:23If you would again another
30:25marker of ER stress.
30:27If you look at some of the molecules
30:30that we know are expressed in islets.
30:32Hormones such as GAD.
30:34They they don't end up with the
30:37right spaces within processes.
30:39They get either hung up in
30:41places like the Golgi or the ER
30:44and and they accumulate there.
30:46We've had a couple papers with my
30:48colleague at Phelps on this that
30:50are either out or coming out,
30:52but it looks like there's processing
30:55deficiencies in both individuals
30:56at risk for type one diabetes
30:59and those with the disease.
31:01If you look at sensing mechanisms,
31:04glucose is,
31:04you know if you think of islet cells
31:06and beta cells as being essentially
31:08factories for producing insulin.
31:10I mean, they're just insulin factories
31:12they have in order to work efficiently.
31:15You know they have to sense.
31:16Glucose, and so.
31:18A colleague.
31:19Another colleague of mine next door.
31:22Actually he started taking a look
31:24at the expression of the molecules
31:26that are both associated with sensing
31:29as well as responses to insulin and
31:31what you can see is things like ATP ace,
31:34gluco kinase.
31:35They're reduced both in individuals
31:39with type one diabetes,
31:40which are the middle column,
31:42but they're also reduced in again.
31:44Individuals with Autoantibody
31:45positive no diabetes.
31:47Yeah,
31:47but at risk for the disease.
31:51So we're starting to stack up here again,
31:55evidence that it's not just the
31:57autoimmunity that's in play here,
31:58but beta cells are abnormal.
32:00Now. Here's here's some other
32:02ways that we've shown that,
32:03and this is a paper we've published in cell.
32:06I'm just going to highlight
32:07one thing in the middle.
32:08Here again, these are.
32:12Tissue site top results.
32:14Looking at insulin,
32:15Glucagon and Samantha Staten staining
32:17so they're the three predominant
32:19hormones that you look at in the island
32:22and with the insulin being in red,
32:24these are.
32:24I know there's only four individuals here,
32:27but this is looking at the insulin
32:29staining and individuals that died within
32:32one week of type one diabetes diagnosis,
32:35and you can see like in the
32:36first column in the middle.
32:37Some people do have a marked
32:40reduction in the.
32:41Degree of insulin positive itself,
32:44but in other cases don't.
32:46So again,
32:46the amount of insulin that you
32:49can find in the pancreas at
32:51onset can vary dramatically,
32:53and it's not everybody is not the 90%,
32:55as I mentioned earlier on as a dogma.
32:59Another thing that we've been
33:00able to do with side top,
33:02and I know Yale has this technology
33:05is we've been able to make panels of
33:08different antibodies and then do.
33:10Look at by pseudo time analysis.
33:13And and by doing pairings,
33:16what we've been able to identify is is
33:19that that at the onset of type one diabetes,
33:22which is that middle column on the right,
33:25I'd like you to just focus on the D panel.
33:28This is islets from individuals
33:30at the onset of disease,
33:32the red.
33:35Column is individuals who had type
33:37one diabetes for seven years or more,
33:40and then the yellow panel on the
33:42left is islets from individuals
33:43without type one diabetes.
33:45And what you can see is that
33:47the answer to type one diabetes.
33:49They're not exactly normal,
33:50and we all based on you again.
33:53Just using 7 antibodies in combination.
33:56So why this is and what percentage
33:59I can tell you?
34:00By different cases,
34:02the percentage that that fit
34:04into these stages?
34:06Can vary quite dramatically,
34:07but we've found this site off
34:10very useful for phenotyping.
34:13Another thing that we've been
34:14doing with site talk is to start
34:17taking a look at expression panels
34:19and identifying early on what.
34:22When do things changes occur in
34:24the Natural History of disease?
34:26So for example,
34:27like on the bottom left of the class,
34:30one HLA that I spoke about.
34:33When does this occur and we're
34:36identifying a whole series of
34:38molecules and just randomly going
34:40through here from beta 2 microglobulin
34:45IPPP? C SK1 is a prohormone processing.
34:50These are all molecules that we've
34:52been able to identify in the Natural
34:54History of disease in beta cells.
34:56Or in islands that that show
35:00abnormalities long before disease onset.
35:03Another thing that we've been able
35:05to use site top is to try and to
35:09densitometric standing up the number of
35:11blood vessels per eyelid and the the
35:14actual diameter of those blood vessels,
35:16and one of the things that we can say and it.
35:20I'm apologize if it's not cleared,
35:22but the the green would be normal cases.
35:25The green line in the green dots,
35:28and then the pink ones magenta
35:30ones are the long term diabetics.
35:33And then the blue are people at onset.
35:35What we can see through this study
35:38is is that islets in individuals
35:40with type one diabetes,
35:42their their blood vessels are
35:44actually shorter and have a thinner
35:47diameter to them versus normals.
35:49So it's almost as if the type
35:51one diabetic eyelid is strangled.
35:53In a way,
35:54it's a very highly vascularized organ,
35:56but in the type one diabetic
35:59case it's not normal.
36:01We've also published this article
36:03in Cell and we have another one
36:06coming out soon there where that.
36:08The eyelets and type one diabetics they
36:10they don't process hormones naturally
36:12and to go through all this in great
36:15detail would would take up too much time,
36:18but one of the things we've been able
36:20to identify is is that in individuals,
36:23both with type one diabetes as
36:25well as at risk for the disease,
36:27they are deficient in some of the
36:30prohormones processing enzymes.
36:31That allow for conversion of
36:34proinsulin to insulin,
36:35and this has been validated in living humans.
36:39This was again through studies of tissue.
36:41In looking at the degree of
36:44of insulin and proinsulin.
36:46C peptide that you could extract from
36:48these tissues and then doing quantitative
36:51PCR and looking for the quantitate,
36:53the amount of the processing enzymes.
36:56But we've again seen this in
36:58human living samples that they
37:00seemed also in the pre diabetic.
37:02Stage have alterations in the C peptide
37:05that amplified by disease onset.
37:08Couple more things occur in
37:10the type of the type.
37:11One pancreas,
37:12one of them is is the
37:14accumulation of hyaluronan,
37:15hyaluron and binding proteins.
37:19They form almost a capsule around the
37:21type one diabetes diabetic islet.
37:24We also have some evidence that suggests
37:27that it too is as a potential marker of
37:31islets that are going to be destroyed.
37:34Or essentially a hallmark for signaling.
37:36I'll just close the beta cell part
37:38by saying there's actually now
37:41about 17 different features that
37:43we've identified that are present
37:46in the auto antibody,
37:47positive pancreas or new onset pancreas
37:50that tell us that beta cells are involved.
37:54It's it's not just the disease
37:56of the immune system.
38:00The last two lessons will go relatively
38:03quickly, but the third thing that I think
38:05we've learned that again wasn't in the
38:07textbooks or is not in most textbooks.
38:10It's that beta cell replication in number is
38:13important in type one diabetes development.
38:16And that actually until
38:19recently it was widely.
38:20If you were to go just particularly like
38:22a transplant audience where people would
38:25do islet transplants and you'd say,
38:27well, how many islands are in
38:29the normal adult human pancreas?
38:31And most people would say, oh,
38:33you know, a million or so?
38:35Well, a collaborator of mine, Peter Butler,
38:39did this study from Mayo Clinic cases
38:41and some in pod cases of a few years ago,
38:44and actually.
38:45Depending on how you find it this
38:47way in this paper was beta cell mass.
38:49Actually, in normal individuals this
38:52is normal individuals nondiabetic.
38:54The amount of beta cell mass in the human
38:57pancreas is varies quite dramatically.
39:00It's not just a standard like
39:03that everybody has.
39:04And here's some very innovative
39:06work that we did from studying.
39:08The pancreas is to take a look at when is
39:13that mass set in life and what we did is,
39:17and we've probably are.
39:19We haven't published an update,
39:20but we probably have six times the
39:22number of cases that are shown here.
39:25But just to cut to the chase,
39:27you really are by about the age of four,
39:30if not earlier.
39:31You pretty much are locked into the number.
39:35Of of islet cells or beta cells
39:38that you're going to have in life.
39:40And unlike some of the mouse
39:42models where if you have a mouse,
39:45if they become pregnant or
39:48have pancreatic injury,
39:49the mice have a tremendous
39:52ability to recover.
39:54It's not so quite that way in in humans,
39:57and so I think we tend to think of
39:59this as almost a growth curve like
40:01situation where sometime in early life,
40:04and we're not sure why is it microbiome
40:06driven? Is it nutrition driven?
40:08Is to genetic driven?
40:10But you end up with some number
40:13of islet cells and that will
40:15largely be what you have in life.
40:18And we that's important.
40:19Oh,
40:19and here's an example of some unpublished
40:21data from a person down the road from you,
40:23Susan Bonner, where where?
40:26Again,
40:26that's what she did was take
40:28a look at two things.
40:29One, she looked at pancreas weight,
40:32which is in the blue lines
40:34versus the beta cell.
40:37Number in that particular pancreas.
40:40And for normal individuals,
40:42your pancreas continues to grow
40:45on until about 25 years of age.
40:47I've not shown the whole lifetime data here,
40:50but at about 25 years of age,
40:52your pancreas stops growing.
40:53But in terms of the actual beta cell number,
40:57that again stops at around
41:004-4 years of age or so,
41:02and the mechanisms that control
41:05that are undergoing investigation.
41:07So one of the things that we believe,
41:09and it published now on is is
41:12that when why we think islet
41:15cell numbers are important is
41:16is that perhaps early in life you're
41:18the amount of beta cell mass you have.
41:21It is fixed and whether or not you have
41:24a high beta cell mass and intermediate or
41:27low will form a degree will be important
41:30in terms of diabetes development.
41:33Both type one and Type 2.
41:35In that if you have a high beta cell mass,
41:37maybe be more resistant disease
41:39in the low lower beta cell mass,
41:42more susceptible to disease.
41:45So in the last five minutes of the
41:46talk here I wanna just leave it out.
41:48We started small and now we're going big.
41:50Is that type one?
41:51Diabetes is also a disease of the pancreas.
41:54And as I was sharing with one of you
41:57this morning, we are one of the lab.
42:00This was actually known back in
42:01the 1960s from autopsy material,
42:04where but it was.
42:06It was reports that said well in people.
42:09With some cake cases of diabetes,
42:12more often insulin requiring diabetes,
42:15their pancreas appeared to be smaller.
42:18But what we published this a few years
42:21ago in JAMA was because one of the
42:24mythology techs came to me one day and said,
42:27hey.
42:27Do you ever notice that the pancreas from
42:30the type ones there's so much smaller than?
42:34The normal set we get.
42:36And so we started going back and
42:38analyzed it and found in published
42:40this paper because it was true
42:43at the type ones were smaller.
42:45But the reason this ended up in jam
42:47is that middle middle group that even
42:49people without type one diabetes but at
42:51risk for disease they had a smaller pancreas.
42:54And if the picture is worth 1000 words here,
42:57I'll just show these two pancreata,
43:00one front.
43:00They're both from their age matched
43:03our age similar 1413 year old,
43:06similar BMI's,
43:07but if you see the top pancreas,
43:10its weight is about half of that.
43:13Of the normal pancreas down at
43:15the bottom and what you'll see
43:17is most of the losses actually,
43:19at the tail of the pancreas.
43:20So to the far right and far less at
43:22the head of the pancreas and the
43:24tail of the pancreas is the region
43:27that usually has the most highest
43:29number of insulin producing cells,
43:31and then we publish this as a
43:33follow up with far bigger numbers.
43:35But if you look at what we call relative
43:38pancreas weight or TPW on the left hand side,
43:41what you can see is is that
43:42the type one pancreas.
43:44And is about 1/3 to half the size on average.
43:48At at onset it's about 25 to 35%
43:52and within two years it'll be about
43:5435% to 50% reduced type 2 diabetes.
43:58It seems to more of a type
43:59one effect type 2 diabetics,
44:01maybe a tad bit reduced,
44:03but nothing like the type one
44:05and has noticed noted earlier.
44:06The greatest loss if we take the organ
44:09in segmented into head body tail its
44:12smallest in grace reduction in the tail.
44:15Uhm,
44:15we were all always,
44:17as I'm sure you all are in terms of
44:20pathology and working with tissues.
44:21People said, well,
44:22how do you know that that's real or not?
44:24An artifact of of your
44:26processing or or something?
44:29So we published with Mike Halloran,
44:31Martha, another colleague,
44:32I a study of about 300 patients
44:36where we did Mris of the individual.
44:39And again, I'm just going to
44:40highlight this sort of sake of time.
44:42If you blind analysis by radiologists.
44:45But if you look at the pancreas
44:47in blue here of individuals with
44:49recent onset type one diabetes,
44:51you see they're quite reduced
44:53relative to the control population,
44:55which is the green bar.
44:57And the auto antibody positive were
44:59also reduced as we assume from the other
45:02studies about what was interesting and
45:04we still don't have exactly explanation.
45:06But even from first degree relatives,
45:09that's FDR.
45:11With autoantibodies no autoantibodies,
45:13even their pancreas was a little smaller
45:16relative to age matched controls.
45:19Suggesting that there might even
45:22be some genetics in play here.
45:25Uhm, we know that the exocrine
45:28function is also decrease.
45:29We've looked at amylase,
45:31life pace and then in this case
45:33I'm showing data on trypsinogen.
45:34They're all reduced in both the pre
45:38diabetic state as well as at the time
45:41of disease onset or established.
45:43So exocrine functions declines and
45:45the other thing that we've noticed
45:48as have others that if you just
45:51look at exocrine infiltrates now
45:53this is not pancreatitis chronic.
45:55Pancreatitis but just exocrine infiltrates.
45:58They seem to be higher in type
46:02one diabetes patients.
46:03Rather your new onset or.
46:07Long established Type one diabetes,
46:09then control individuals suggesting
46:11that again, it's an interplay,
46:14but something is abnormal
46:15in the exocrine pancreas.
46:18So just in the last couple of slides
46:20here I want to leave you with a kind
46:21of a situation that we're working on.
46:23Moving forward is is we're faced
46:25with a major burning question here,
46:28and this is something that one
46:30of your own Kevin Harold and I.
46:32We published an article together
46:34almost a decade ago now where?
46:38We we asked this question and I
46:40should say that this question was
46:42actually asked about 30 years prior,
46:45but we asked it again is type
46:48one diabetes as a result from
46:50an autoimmune attack,
46:51meaning where the immune response
46:53is doing what it's supposed,
46:55not what it's supposed to do,
46:56meaning it has a loss of
46:58tolerance to these beta cells,
47:00both central and peripheral, and that.
47:03It's destroying the beta cells or.
47:06Is it with through the evidence that
47:08I've shown you the contributions
47:10of the beta cells in the pancreas
47:12that actually the numune system
47:13is doing what it's supposed to do?
47:15That when you have beta cell
47:17dysfunction and things like metabolic
47:20stress or that inflammation.
47:21That it's actually destroying
47:23these and which occurs first.
47:26So this is a burning question that
47:28we're spending a lot of time on
47:30now and think that it could really
47:32help on intervention and
47:34biomarker analysis, but without it's
47:36a little difficult to study in the
47:38humans 'cause we only have cross
47:41sectional sections are announced
47:43system not longitudinal like you can
47:45do in fortunately do in mouse models.
47:47So I think we're on time here,
47:49but again, there's so many people.
47:52To thank UM that are part of the team here.
47:55It takes a huge operation to like I say,
47:58collect all of these.
48:01Organs and tissues for the studies.
48:02So I want to give them appropriate
48:05knowledgement and again,
48:06thank you for listening and I'll
48:07be happy to answer any questions.
48:11Thank you very much, Mark,
48:13and that this is a you know,
48:14fantastic seminar.
48:15So now is open for question,
48:18and while other you know you can just
48:21because we cannot steal so you can
48:24either just type you know into the
48:27you know question and answer you know
48:30chat box or you can just speak up.
48:33So before other people ask maybe I
48:35will ask one question Mark and this
48:38is related to beta cell regeneration.
48:41The overall concept,
48:42for example through all these,
48:44you know the the donor tissue from pancreas,
48:47have you?
48:48You know your team have gained
48:50additional insight into the
48:52potential for beta cell and dodge,
48:54and I mean endogenous beta cell regeneration.
48:57All the precursor.
48:58In other words,
49:00the stem cell of the potential bid cells.
49:03Have you gain additional insight?
49:05Yeah,
49:05so let me give one little insight about this.
49:09Again, the the world grew
49:11a lot of encouragement.
49:12Comment on the announcement about two weeks
49:15ago on Monday of a study by Vertex Pharma,
49:18where they've been studying,
49:20it grew out of Doug Melton's lab at Harvard,
49:24and they have a now a stem cell line that
49:27they've that's been put into. Patients.
49:29It you transfuse it into the they,
49:32transfuse it into the liver, and the
49:35patients have to take immunosuppression,
49:37but at least the after 90 days these
49:40individuals are starting to produce insulin.
49:43Or or as measured by C peptide and
49:45the need for taking less insulin.
49:48So regenerative medicine stem cell is alive
49:51and well in type one still has challenges,
49:55but now to your question
49:57about endogenous replication.
49:58That's have been a bit more of a challenge.
50:01We do understand a lot of this works
50:03been done by individuals at Mount Sinai,
50:06but there's these molecules that
50:08called Dirk 1A and Dirk 1B.
50:10They're like breaks.
50:11If you would that.
50:13Go on in and inhibit the beta cells
50:17from replication and an adult,
50:20uh, islet cell.
50:21Now there's a lot of efforts to try and
50:25develop ways that you could deliver.
50:29Molecules that are that are capable
50:31of essentially removing those breaks,
50:33and there's I know of at least
50:35four compounds than one.
50:36Most common is called harmine that do that,
50:39but the challenges is how do you X vivo
50:41deliver them and get beta cells specificity?
50:44A lot of these.
50:46Molecules that are lindwood induced
50:48replication of beta cells in the body.
50:51They they have off target effects.
50:53So like you know you,
50:55you don't necessarily want you
50:58know your cardiac replication,
51:00hepatic replications,
51:01stuff like that so that that field
51:03still is a little too long an
51:05answer to say people are trying,
51:07but it's a little bit of a challenge to get
51:10specificity and targeting to the pancreas.
51:14Saints Mark now I have a question
51:16from a Kevin and you know he say.
51:18Can you say anything about the
51:20features of the beta cells in
51:22long term surviving beta cells in
51:25someone with type one diabetes?
51:27Yeah, so that yeah, that's that's
51:30a great question and we we are now.
51:32I have 12 different cases that
51:35are just what Kevin asked for.
51:37They are longstanding.
51:39They've had type one diabetes at least 20
51:43years, and we're running those source.
51:44I talk panel. Right now,
51:47and I hope you know, maybe by the
51:49end pod meeting that will stand it.
51:50So just serve virus stands that
51:54same Susan monitor weird that I
51:56mentioned with the growth charts,
51:58they've been stunning.
52:00Dozens and dozens of patients that had
52:03type one diabetes for at least 50 years, 50.
52:07They're called medalists and what she
52:10published was essentially, you know.
52:13Again, it's central dogma is is
52:15that within a few years all the
52:17insulin producing cells are gone,
52:18wiped out the like.
52:19She's found that if you have a whole
52:22pancreas and look hard enough you'll find.
52:25Insulin positive beta cells.
52:28Decades after disease onset.
52:30So they may autoimmune response for some.
52:32Whatever reason.
52:33It never goes quite completion.
52:35It never wipes out all of the beta cells.
52:38So Kevin's question is a great one.
52:41So what makes though? Is it?
52:44It almost is a chicken and egg thing there.
52:46What makes those cells resistant
52:49to final destruction?
52:51What?
52:51What property do they have?
52:53And if we knew that that that
52:55might be very informative.
52:57To you know, a clinical trial or
52:59something to do to make a like a bait.
53:02People, sometimes called beta guard.
53:04Or is it the immune?
53:05What is it some problem with the immune
53:08response where the immune response
53:09just doesn't bring it to completion?
53:11So it's a great question.
53:14And we're working on but don't
53:15have an answer yet.
53:17Thanks, Margaret.
53:18Now we have question from Johnson
53:20Art and it's a current belief
53:23that autoantibodies to eyelids
53:25are secondary to the disease,
53:27rather than having a causative role.
53:31Yeah, another great question so.
53:35It I one thing people agree on
53:38is that autoantibodies are the
53:40smoke representing the fire,
53:42and that they they're used as tremendous
53:45markers of disease prediction,
53:47identifying people at risk.
53:50The assays have gotten really good now.
53:54And so they're used as a uh,
53:56as a biomarker is unquestioned
53:58now in terms of pathogenic Lee.
54:01What they do?
54:02There's few people that believe the
54:05antibodies in and of themselves
54:07play a functional role in terms
54:10of destruction of beta cells,
54:12save through cytolytic mechanisms,
54:15for example.
54:16But what has there is evidence
54:18to show is is that these are
54:21very effective antigen producing.
54:24Uh, presenting cells excuse me
54:27Apcs and so that's right now
54:29pretty much the state of the art
54:31in terms of functional role.
54:33And I should say,
54:34and Kevin knows this,
54:35he was part of the study.
54:37There has been one of those
54:39clinical trials I mentioned the
54:40beginning and people probably are
54:42familiar with Rituxan mab you can.
54:45Uhm,
54:46delay the progression of type
54:48one diabetes after onset.
54:51The loss of the beta cells
54:53by using that agent.
54:55Rotax map and kind of consistent
54:57with pathology.
54:58It seems to work better
55:00in younger individuals.
55:01Sort of consistent with that B
55:03lymphocyte being may be pathogenic.
55:05Lee involved so.
55:08There there are hints that B cells
55:11are are involved in the disease pathogenesis,
55:15but antibodies,
55:15not so much.
55:18Thanks, now I have Caesar Laura
55:20Manuelidis that her hands up Laura.
55:24Please go ahead to ask their questions.
55:26Great, I was just thank you for your talk.
55:28I thought it was wonderful and very
55:29clear. So my first question is sort
55:32of broad question because what really
55:35insights or what ignites these sort of
55:38stress of of the diabetic response,
55:40especially over the age groups.
55:41So one of my questions was
55:43do you think that there's a role for
55:45any viruses or COVID viruses in sort of?
55:48Inciting some cases of diabetes.
55:51Early diabetes. Insulin was
55:54the second question, is this
55:55sort of more detailed question
55:57that I let cells are extremely
55:59high in pryon protein?
56:01And in fact, prime protein is
56:03involved in neurogenesis
56:04in the very early stage.
56:06That's where it's critical
56:06stages and synopsis in Genesis,
56:09and I was wondering if you
56:10studied any prime protein in
56:11some of the early cases before
56:13the age of four versus later
56:15to see if the expression really
56:17varies or is some indication
56:18of what's happening in terms of development
56:21of islet cells. Thank
56:23you, oh thank you.
56:25Here's the challenge.
56:26I gotta remember both questions.
56:27Let me send the first one.
56:29So invite role of environment
56:31and type for decades.
56:3350 years people have looked,
56:35tried to look for the environment,
56:37contribution to diabetes.
56:38There's a lot of evidence were
56:42environment is playing a factor one.
56:45If you look at incidence rates,
56:47they're going up.
56:48Can't be explained by genetics in
56:50the like button and the the NIH for
56:52about 18 years now has had a huge
56:55environmental study where they've
56:56looked at like 160 different things
56:59in the environment from dietary.
57:02Lifestyle practices yeah no smoking guns.
57:08Voice speaking about viruses
57:10covert virus is unknown.
57:11Viruses viruses at the security
57:13bug they've been. They've taken samples
57:15and unjust blast sequencing to try and
57:18identify viral sequences, saying it,
57:21it's it's murky at best. No smoking gun.
57:24Now to the quote kovid question.
57:26We've been involved and I've had a paper in
57:29cell and then Lance it within the last year
57:32and their evidence there is again murky.
57:35There's clearly an association.
57:39Between diet, diabetes and COVID,
57:41and in fact I'm working with,
57:43uh, Ruth, Montgomery and.
57:47David Hafler at your institution.
57:50We're part of a big consortium and
57:52this is one of the questions that
57:54we're looking at is the relationship
57:56between diabetes and COVID?
57:57Clearly you're susceptible for poor
58:00outcomes if you have diabetes?
58:02We've looked at like 54 pancreases.
58:06From people who died from cold that
58:08and tried to show that the there's
58:11a relationship between positive
58:13ITI for COVID in the pancreas and
58:16diabetes and can't find it.
58:18We've set up in vitro culture systems,
58:21infected beta cells and islet cells,
58:24and those you the number percentage of beta
58:27cells you can affect is like 2% or less.
58:30Very inefficient process.
58:32We don't believe that.
58:33There's people that believe that
58:35COVID induces diabetes so far.
58:38I don't that's unproven at best,
58:41but it would take longer to answer that
58:44it would now to your Brian question,
58:47we published a paper about two months
58:49ago in this journal called Diabetologia,
58:51where we've looked at that and
58:53just nailed it.
58:54Just like what you said is that
58:56its expression is much higher in
58:58the Type 1 pancreas.
59:00And even in the Autoantibody positive
59:02pancreas than in the controls.
59:04We have not, however,
59:05looked at it as a function of age,
59:08and I'm going to write that down and
59:10then try and look and look at that
59:13after to see you know if we if we parse
59:16that out or at least like I can't,
59:17I don't recall.
59:18That we did it, but yes, you're right.
59:21That is a.
59:23Another factor that seems to be associated,
59:25thanks another question from Doctor Merati.
59:30So she's asking actually say how the
59:33collection of the pancreas is organized?
59:36Rapid autopsies? Specific pancreas
59:39collection, biopsy, bulbank.
59:40This is more relatable to empire.
59:43Yeah, so that's a great question.
59:45So no, although none of these
59:47samples that I showed you or none
59:49of our studies are with autopsy,
59:51they are all with transplant.
59:54Organ transplants,
59:54So what happens is we worked out
59:57with all of these doppio's in the
59:59United States that the same surgical
01:00:01recovery team that's taking the heart,
01:00:03lung, liver, kidney.
01:00:05Uhm, four.
01:00:07Then the next thing they do is
01:00:09take the pancreas for us so it's
01:00:12flushed and it's shipped here
01:00:13as if it's going for transplant.
01:00:15So although the processing is is done,
01:00:18just as if that the average
01:00:21time between cross clamp and
01:00:23delivery here is about 13 hours.
01:00:25And so they're all the pancreatic biopsies
01:00:29of living subjects are not thought ethical,
01:00:33and for good reason.
01:00:34I mean,
01:00:35it was tried again about 10
01:00:37years ago and had bad outcomes.
01:00:39You don't biopsy the pancreas
01:00:40unless you have two in.
01:00:42I'm sure I'm all I'm doing is
01:00:44telling you what you know.
01:00:45In the autopsy tissues you
01:00:47know on the few times those we
01:00:50are getting using park obit.
01:00:52For those cases we were bound to
01:00:55use for COVID for the most part,
01:00:58but we are recovering.
01:01:00On pancreas for for transplant from
01:01:02transplant cases where they once
01:01:04had COVID but are now PCR negative.
01:01:08Thanks, we have a question from a.
01:01:11I think wins hands down wins.
01:01:14You know you can ask your question please.
01:01:16Yes, you mentioned that the blood
01:01:18Kappel Aries in blood vessels
01:01:20in like the pilots breakdown.
01:01:23How does that work?
01:01:24What do you think is happening? So
01:01:28yeah, that we don't know yet.
01:01:30And again I was my second
01:01:31time we're going to use this.
01:01:33We don't know exactly the there's a lot
01:01:36of there's a lot of speculation about
01:01:39the the impact of having a loss of
01:01:42insulin at the self communication level,
01:01:45and that again you start out in life.
01:01:47You have these essentially factories
01:01:49that just produce a lot of insulin and.
01:01:52It's both a trophic factor and
01:01:55has so many other.
01:01:56Properties that there's the speculation is,
01:01:59although it's unproven
01:02:00that as you lose insulin,
01:02:03the insulin producing cells that that'll
01:02:07have downstream effects and one will
01:02:10be again vasculature or capillary.
01:02:13Shared with one of your colleagues
01:02:15this morning I turned into grant
01:02:16two weeks ago where we're going
01:02:18to try and take a look at this
01:02:20functionally and figure out why it is.
01:02:23But yeah, I.
01:02:25I should say, and I didn't put in here.
01:02:27The other thing is,
01:02:28is that people have been looking
01:02:30at a lot of the neuronal.
01:02:33Yeah, impacts and that are
01:02:35occurring there and those networks
01:02:38also appear to be disrupted.
01:02:41OK, alright so then another
01:02:45question from David Rain.
01:02:47So what does it cost to get
01:02:49this transplant pancreas?
01:02:51Yeah, so if you're going or pancreas
01:02:54goals for clinical transplant,
01:02:57the price can vary dramatically
01:03:00from 28 thousand, $35,000, or more,
01:03:03but we've negotiated with with all the
01:03:07opos either individual contracts or
01:03:09through research and intermediaries.
01:03:11We obtain the pancreas, spleen,
01:03:14peripheral blood and started
01:03:16tissues for about $8000 a case.
01:03:208 So we get a research discount.
01:03:23If you would say.
01:03:24But we we are processing we collect about.
01:03:28125 pancreas is a year, so it's a it's a lot.
01:03:35OK thanks Mark, I know the time is
01:03:38we have last question from Paul
01:03:40and so I think his question is,
01:03:43given the microvascular pathology that
01:03:46characterized the clinical course,
01:03:48is there damage to the other blood
01:03:51vessels in other organs? Yeah,
01:03:53so the answer is yes and that this again
01:03:56goes back to that grant I just put in two
01:03:58weeks ago where what are moving forward,
01:04:01what we're proposing to do
01:04:03is collect hearts and.
01:04:06Uh, different vascular peripheral
01:04:08vascular tissues from individuals
01:04:10with type one diabetes, type 2 diabetes,
01:04:14and then people with cardiovascular
01:04:16disease that that don't have either
01:04:18form of diabetes and we're hoping
01:04:20to answer that question because,
01:04:23again, this kind of goes back to my
01:04:25earlier answer about insulin loss.
01:04:27Is is that?
01:04:29We we hope to identify differences
01:04:32between type one and type 2 diabetes,
01:04:35where again on the type one.
01:04:36You don't have your endogenous insulin
01:04:39production, where is in the Type 2.
01:04:40It's going to be more on insulin action, etc.
01:04:43So again,
01:04:45a great question and I hope to
01:04:48you know within a couple of years
01:04:49we'll have some answers there.
01:04:51OK with that and I was just
01:04:54really fantastic lecture.
01:04:55You know mark? I mean I, I just said,
01:04:58you know this is a really sad example.
01:05:00Say how to you know really using
01:05:02human tissue to discover all this
01:05:04new knowledge is and this is great.
01:05:06You know we wish you well and
01:05:09by selecting impact and study.
01:05:10And once again thank you very much
01:05:13for giving us the lecture and we will.
01:05:16I will you know when this all open up
01:05:19we want you to come here to visit us.
01:05:21Thank you, have a lot of connection
01:05:23at a year.
01:05:24You know, as you know you might feel OK.
01:05:26Once again, thank you very much Mark.
01:05:28And then we'll we'll be in contact.
01:05:30So Manjula,
01:05:30who is the director of our grandma man?
01:05:33Do you have any last word?
01:05:36No, really very exciting talk and
01:05:39there are many more questions,
01:05:41but we are out of time.
01:05:44OK, thank you again, Mark, thank you.
01:05:46Thank you. Have a nice day markets you too.
01:05:50OK, goodnight,
01:05:50see it's always.