Lessons from the Human Pancreas: Rewriting the Textbooks on How Type 1 Diabetes Develops
November 11, 2021Information
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.