cc >> I can't tell everyone what
a pleasure and honor it is to be back at the University
of Wisconsin to give Grand Rounds today.
I really appreciate the invitation to have
an opportunity to talk to you a little bit about the clinical
trial work that we're doing at the University of Minnesota,
as well as across the country and internationally.
And I'm hoping that I'll be able to bring you up to speed
on some of the newest things that are happening
in that field. I felt like it was important
to kind of give you an idea a little bit about what was
happening and what I've done since I left Wisconsin,
with a little bit of a twist on the Big 10.
And as Dave mentioned, I did go to Rainbow Babies, and I had
a great fellowship training experience.
We really have enjoyed the upper Midwest, and so we
stayed in Big 10 country, which is both good and bad.
I had a great fellowship training experience.
However, I was inundated with this guy in the state of
Ohio which was really annoying, after being here in Wisconsin,
as my first Big 10 school, and sort of being partial
to Bucky. So I'm really lucky and
fortunate about the position I've been able to take over
at University of Minnesota. We're really enjoying
our time up there. But of course, you've got to
deal with this Goldy the Gopher all the time.
That's why it's such a treat to come back, because I really
have a place in my heart for Bucky and Wisconsin.
And I thought it was important to also let you know about
some of the changes in my life personally, and also as
an excuse for not showing up for seminars, which I still
feel bad about. But I did have a good excuse.
This is Allison Nathan. She is now 2-1/2.
And this little Colin here, who was born a few days after
the start of seminars. But I do again apologize
for not being able to come down for seminars.
And here's Colin just a few weeks ago.
So really, our lives have really been enriched by these kiddos.
So what I'm hoping to do today, over the next 45 minutes, or so,
is to really be able to bring you up to speed, review a little
bit about the pathogenesis behind Type 1 diabetes, and talk
a little bit more about past history of prevention trials,
and what we're currently doing with Type 1 diabetes TrialNet
to try to, again, prevent or provide early therapy for
patients that have recently been diagnosed.
And along the way, these are the objectives that I'm hoping
you're able to obtain. The first is to learn
the importance of both genetic and environmental factors,
and the pathogenesis of Type 1 Diabetes.
The second is reviewing the recent trends regarding
prevalence and incidents. And we'll talk a little about
the trends that are showing in increased incidents
of Type 1 Diabetes. Third, is going to be talking
about the different stages during the natural history,
or what we believe the natural history to be, that provide,
really, an opportunity for intervention.
And then lastly, just to be able to recall just a few of the
studies that we have ongoing for patients of yours, if
they're interested in enrolling in some of these studies.
So first off, I thought it was important to talk a little bit
about where we've come in Type 1 Diabetes.
And this is Frederick Banting, who was the primary discoverer
of insulin. He and his student,
Charles Best, in Toronto identified an extract from the
pancreas of dogs that eventually led to the discovery of insulin.
And that was a really, obviously groundbreaking change for these
patients with diabetes. Unfortunately, we didn't have
a way to actually provide a lot of insulin for patients
of that time. So we moved to actually giving
them pig insulin, and insulin from cows, which again, provided
more insulin for the patients that needed it.
Unfortunately, there was still limited supply.
And there were allergic type reactions to that insulin.
And eventually, we were able to come up with recombinant
DNA technology, which is how all the insulin is made now.
And that's really provided insulin to everyone
that's needed it. We have much better ways
of testing blood sugars now and monitoring disease.
Very small amounts of blood are needed to check blood glucoses.
We no longer have to test urine for glucose, or even taste urine
for glucose, which was what they used to do way back when.
We've got insulin pen devices. We've got insulin pumps.
And we have wireless or tubeless pumps that provide insulin
without any attachments. And then finally, most recently,
we have continuous glucose monitors that provide real-time
evaluations of interstitial glucose levels to help with
glycemic control. So we've really come a long way
in terms of how we treat Type 1 Diabetes.
And this has been important, because we've also learned more
about complications of long-term diabetes, and what those mean
for people that don't have good control.
And you can see in this graph, from the diabetes complications
trial, that your risk of all these microvascular
complications: retinopathy, neuropathy, and nephropathy,
as well, all go up as your hemoglobin A1C goes up
over time. So when we're thinking about
diabetes, we really want to design strategies to try
to keep blood sugars as normal as possible.
Keep your hemoglobin A1C as low as possible
for these patients. Now unfortunately, that does
come at the cost of having frequent hypoglycemic events, so
as you're hemoglobin A1C levels get down to a more normal range
or physiological range, the incidence of hypoglycemia
goes up. So what we're really trying
to do is balance, trying to keep normal blood sugars, reducing
the risks of complications, but also reducing the risks
of hypoglycemic events. So with that as a bit of
a backdrop, let's just talk very briefly about Type 1 Diabetes,
and then we'll talk a little bit more about some of the studies
that we're doing. Type 1 Diabetes is an
autoimmune mediated destruction of the beta cells within
the islets of the pancreas, which results in loss of insulin
secretion. Also you know the diagnostic
criteria, or clinical symptoms that are associated with
Type 1 Diabetes are polyuria, polydypsia, weight loss,
and about 50% of children will present in diabetic
ketoacidosis. Probably most importantly when
we talk about prevention studies is that we can identify markers
in the bloodstream that tell us this is an autoimmune process,
so somewhere in the neighborhood of 90-95% of new onset patients
will have at least one diabetes auto-antibody
in their bloodstream. The reality of living with
Type 1 Diabetes is that we can care for it actually quite well
right now, and people live really relatively normal lives.
But it is a change in their life, no doubt about that.
It's a life changing event, that most kids and adults
are checking their blood sugars somewhere between four
to six times per day. There are risks of hypoglycemia
and long-term complications, as we mentioned, as well as
acute complications. And so we really haven't,
although would we have come up with great ways to treat
the disease, we haven't found the best ways to prevent
the disease from occurring. Now what's been interesting
and a phenomenon that's been happening probably over the past
30 to 40 years, is there have been signs that the rates
of Type 1 diabetes have increased both in the
United States and worldwide. We have, as a country, we really
haven't been as good as the Europeans in tracking and
monitoring Type 1 Diabetes. They have much better designed
registry programs. They're doing much better jobs,
I think, in tracking the incidence and prevalence data.
But we have a new study that's going on right now, which is
tracking the information in about five different centers
across the country. So this is some recent data
that's come out. In 2001, there was a prevalence
of about one and a half cases for every thousand youth
up to the age of 18, and the incidence for Type 1 is about
20 cases for every 100,000 person-years.
Now when you compare that to previous data, that was back
from the 1980s, and some small registry programs in different
places across the country. There is an increase.
It's up from somewhere in the neighborhood from 12-15 cases,
which was the incidence back in the 1980s.
And the fastest growing population are younger children.
More recent data from Colorado, also shows this increase
of about two to three percent per year.
And when you look globally, that's also what you see
in most global registries, about a two to three percent increase
per year. And this is some data that
comes out of Oxford, which I wanted just to point you to this
younger aged group here, this 0-4 years, and their incidence,
that's been slowly climbing over the past 20 years.
So it is becoming even more of a problem.
So I'm going to try to put this into a very brief description
of why diabetes occurs and why it doesn't occur, although
this is really an exploding area and we're still learning
a lot more about it. So what we know is that there
are certain genetic markers that predispose you to risk.
Previously, it was thought that the HLA complex probably gave
you most of the risks, and those was really the primary genes
that were responsible for inducing genetic risk.
Well, we now know that there are probably many more genetic
markers and many more genes that are involved in the pathogenesis
here, that we don't completely know yet.
As I mentioned before, this is an autoimmune disease, and there
are several different cell types within the immune system
that participate in this. So Type 1 was previously
thought to be exclusively a T cell mediated disease.
We now know that, as I'll show you in a minute, B cells
also play a very important role in the pathogenesis.
We also think there is a environmental insult that causes
the disease to proliferate, and this autoimmune process
to sort of spiral until-- or initiate this autoimmune
process, which leads to the eventual loss of beta cell
function. And lastly, we now know, or
we think again, that this is more of a gradual process that
probably occurs at least over months, and probably over years
in several people. With that knowledge, that really
provides us an opportunity to hopefully intervene in some
of these high risk patients, or patients that do have
evidence for autoimmunity. So again talking about the
risks conferred by genetics. About half of the genetic risk
can be explained by the HLA complex, specifically the
Class 2 sub-region. And the most important
alleles there are the DR3 and DR4 markers, so as we go through
some of the studies that we're doing, we'll talk about,
that's one of the screening tools that we're using for some
patients to look for the highest risk population.
There are some other alleles that also impose risk.
And there are also parts of alleles in the HLA complex
that actually provide protection against developing Type 1
Diabetes. There are a few other genes, in
particular the insulin gene, or actually an upstream promoter
on the insulin gene that probably confers about 10%
of the risk for Type 1 Diabetes. And this really speaks to the
concept of lymphocytes that escape thymic regulations.
So people that have smaller tandem repeats in this promoter
region on the insulin gene, they actually have a higher
incidence of diabetes. So the thought is that they
escape normal regulation, and that they're involved
in the pathogenesis for Type 1. There are probably several
other genes, CTLA4, which we'll talk about at the very end
of the talk, as well as several others that have been proposed.
And there has been some associations and some studies,
and it hasn't been found in others.
So we're still trying to learn more about the genetic risks.
I mention that allele. So who's at greatest risk?
This just shows you, like within families, that the risks
of diabetes go up if you have a first-degree family member.
Important here is that most new onset cases occur
in families that don't have any history of Type 1 Diabetes.
It's about probably 85-90% of children that develop Type 1
don't have a family history. However, in terms of trying
to learn more about the disease and prevention strategies,
this is the population that we really want to target,
because these are the highest risk patients that we know of.
So in the general population, your lifetime risk is somewhere
in the neighborhood of 1 in 300 to 1 in 500.
And if you're a child that's born to a mother with Type 1
Diabetes, you have a risk of about two to three percent.
And if you're father has diabetes, that risk goes up.
So there are probably some gender specific genes
that are involved there. That risk is closer
to six to nine percent. On average, it's about a
five percent chance if you have a sibling with Type 1 Diabetes.
And if you have an identical twin who has Type 1 Diabetes,
your risk is 50%. Now I think that's really
interesting because that also speaks to the fact that there is
some environmental trigger here. Otherwise, we would expect
to see that to be 100%. And if you share this high risk
allele marker, your risk goes up by five fold compared to
the normal risk. So again this high risk marker
is present in almost all patients, or at least Caucasian
patients with Type 1. Now this is what you typically
would see in most cases, if you were able to get a pathology
slide of the pancreas. I felt I had to add at least one
pathology slide, just building off of problem conference
history. So this is what you would
typically see. And these slides come from
patients that were very ill during the time of diagnosis,
from several years ago, who eventually died.
And what you see is this lymphocytic infiltration of the
pancreas, specifically in the islets.
These are the beta islets that are stained red here.
And these lymphocytes are primarily T cells, but there's
also B cells involved here. And what's happening on a
cellular level, in a nutshell here, is that you have these
presenting cells. So in this example as a
dendritic cell, interacting with naive T cells.
And this is sort of how the process begins.
The important interactions that they make here are with
this MHC peptide, which is where the antigen is presented
to the T cell. That binds with this T cell
receptor, but there are also very important co-stimulatory,
secondary co-stimulatory signaling that occurs.
And this example between CD40 and CD154.
And that co-stimulatory reaction or communication is very,
very important. So there are both stimulatory
communications, but there are also inhibitory communications,
which I'll discuss more towards the end, when we talk about one
of our intervention studies. As this process occurs, there
is release of cytokines, as in this example, which changes
this naive T cell that is more of a TH1 phenotype.
This TH1 cell then is responsible, or it starts
producing more inflammatory cytokines, which bring other
cells into the area, other cytotoxic cells into the area,
such as macrophages, more cytotoxic T lymphocytes.
And this is what brings that autoimmune process and
inflammation to the beta cells, which eventually leads to
the destruction of those beta cells.
So I mention that B cells, we now know are also very
important, primarily acting as, although they do produce
antibodies, they're also very important as an antigen
presenting cell. So this again, interaction
between the MHC receptor and the T cell receptor,
as well as its co-stimulatory reaction occurs, which leads to
the production of inflammatory cytokines and recruitment
of other cells into the area. The environmental factors,
again, most of these are still not completely understood.
We believe that there are environmental triggers,
but we don't know exactly what those are.
If there are at least one that's identified, there are probably
going to be several more. So viruses have been one of the
things that have been implicated particularly Cocksackie viruses,
but several other viruses, as well.
There are nutritionally proposed risk factors.
In particular, milk, and that's part of the trigger trial
in high risk infants, using a predigested formula,
or an elemental formula, versus a cow's milk formula
to see if you can prevent Type 1 in those children.
And that data is still pending. There has been protective
effect, or a belief that there is a protective effect in
breastfeeding. And that has been shown in a few
studies, as well as timing of solid foods that are introduced.
That may also be a risk factor in high risk groups.
And there are probably other environmental toxins.
So the antibody response, and what we've seen and learned
a little bit about in high risk individuals.
These are first-degree relatives of patients with Type 1
Diabetes. The more numbers of antibodies
that you develop over time, the greater your risk
is for developing Type 1. So again, these are first-degree
relatives. And you can see that at about
five years, your risk of developing diabetes is about
25%, or so, if you have one antibody.
And at five years, if you have two antibodies these are the
antibodies, islet cell antigen, as well as antibodies
against insulin. Your risk goes up as the more
antibodies that you develop. So if you have three antibodies,
your risk of developing diabetes is about 75-80% at five years.
And again, that's one of the main things that we're going
to be using to design prevention strategies.
So if you think about what we believe to be the natural course
of diabetes or Type 1 Diabetes, and think about this being your
full component of beta cells here, if you start off with
someone who's genetically at risk, so let's say they're born
to a family with another member with Type 1 Diabetes, or have
a high risk marker. You start here with a
genetically at risk individual, and then there is some
environmental trigger that may initiate this process and get
this autoimmune process occurring.
And as that occurs, you would start seeing evidence
for cellular autoimmunity, specifically those T cells
that we discussed earlier in the blood stream, which begins
this autoimmune process. You may start seeing markers of
that, this Humoral response in the diabetes autoantibodies
in the bloodstream. And when you get down to about
50% or so of your beta cell mass that's left, you may start
seeing some evidence of metabolic decompensation.
So that would be loss of the first phase insulin response on
an intravenous glucose tolerance test.
And as things progress and that mass gets a little bit lower,
you might be able detect abnormalities on an oral glucose
tolerance test, and that they may not have a normal response
there. Until eventually, when we think
of somewhere in the neighborhood of about 10-15% of your beta
cell mass left, is when you present clinically with
the normal symptoms that we're all accustomed to.
So really, I think each one of these time points represents
an opportunity to intervene with a prevention strategy.
And that's really been done previously.
I was speaking with someone earlier this morning.
Most of the studies that have been done have been built
off of mouse models, where some of these interventions have been
successful in preventing Type 1 Diabetes from occurring in the
non-obese diabetic mouse, or the BB rat, which are animals
that develop diabetes. And unfortunately, there's
been probably close to 200 interventions that have
worked in those models. But in humans that hasn't been
the case to this point, and we haven't seen that same effect.
So all of these have been tried. Some of these are prevention
studies in high risk individuals, and some of these
such as Cyclosporine and Azathioprine have been used
in new onset patients. Importantly, these actually
have worked, at least on a temporary basis.
So the immune effects of Cyclosporine and Azathioprine
have worked on a temporary basis.
The problem with them is that the effect goes away if you stop
them on the medication, or there may be too many toxicities,
such as with Cyclosporine, to continue these patients
on them. So we haven't quite made the
dent we wanted to, but we're getting a little bit closer.
This is a some data from Kevin Herold's group at Yale
using OKT3, which is Anti-CD3, this is more recent data.
This is from their initial study in 2002.
And in using this intervention in new onset patients, what
they found was that the C peptide levels were preserved
in patients that received the Anti-CD3 or OKT3
versus the control group, where their C peptide levels
declined over one year. Now unfortunately, those levels
look like they start decreasing over 24 years.
So even though there was a difference between the control
and the intervention group out here at two years, there was
evidence that this effect seemed to wean over time.
So we don't think it is going to be the exact thing that we need,
but perhaps maybe there's going to be another intervention
at 24 months that may preserve further beta cell function.
So that is a backdrop. Let me talk to you a little bit
about Type 1 Diabetes TrialNet and some of the work that's
going on up at the U of M. So Type 1 Diabetes TrialNet
has three main focuses. One is to prevent disease,
so treat patients prior to the development of T cell
autoimmunity. The secondary component is
delaying the onset of disease, so this would be again in
individuals that have evidence for autoimmunity, have evidence
for antibodies in their bloodstream, and can we delay
or prevent the disease from occurring in that population.
And thirdly is ameliorating the disease in patients
that have developed it. These, again, are patients
that have a much smaller, or reduction in their beta cell
mass. Can we actually treat these
patients to preserve their remaining beta cell population,
to prevent long-term complications,
and also hypoglycemia. So the first study I'll talk
to you about is the natural history study and the Type 1
Diabetes genetics consortium. And these studies are really
aimed at getting a better idea and understanding of what's
happening with the natural history for Type 1, and
understanding the importance of genetic contributions.
This is very important. Number one, it may help us
better define alternative therapeutic strategies.
And as an example of this, many of the monogenic forms of
so-called MODY disease, we've learned much more about those
forms of disease over the past 20 years, specifically the genes
that cause them, and those that allowed us to actually
intervene with some alternative therapies, that have provided
an alternative to them compared to insulin
and are very effective. Secondary is to help us better
identify high risk individuals. Third would be to help us
to better understand the differences between
individuals from different ethnic backgrounds.
Fourth we know that actually some of the co-morbidities and
complications are very different in different individuals, even
with similar types of control. So perhaps this would also allow
us to better understand the risks of complications
long-term. And lastly, to identify gene
interactions or gene environment interactions that are important
to the pathogenesis. So along these lines, this is
the Type 1 Diabetes Genetics Consortium.
Again, the goal is discovering how these different inherited
genes might contribute to the risk of diabetes.
And this study is targeting families with at least two
siblings with Type 1 Diabetes, or children of specific ethnic
backgrounds, specifically African American and Latino
backgrounds. It involves a single blood draw
and they do all kinds of gene array analysis, and this will
be ongoing analyses to look at contributions from other
gene types. The natural history study
is, again, really helping to better define the natural
history of the disease. So the objectives for the
natural history are: number one, characterizing the risk for
developing Type 1 Diabetes in at-risk population.
Number two, is understanding the pathogenetic factors that are
involved in the development of Type 1.
And third, is to develop clinical trials or be able
to offer clinical trials for individuals that have
evidence for autoimmunity. So eligible participants for
this study are again, looking at first-degree relatives
between the ages of 1 and 45. So this would be in your parents
or other siblings, or if you have other children and
you have Type 1 Diabetes, between the age of 1 and 45,
you would also be eligible. And we also enroll second-degree
relatives, a little bit younger age there, so even extended
family members, where may still be an increased risk.
The screening for this study really involves a single
blood draw, again. And it's really just looking for
presence of autoantibodies. If you do have presence for
autoantibodies, you would then be eligible for the secondary
phase, which is more extensive metabolic testing.
If you don't have evidence for antibodies, you can come
back and have yearly follow-ups to repeat those antibodies.
So if look at the kind of the course of this study,
phase one is just the screening for the auto antibodies.
If you have evidence, on two occasions, of autoantibodies,
or two separate autoantibodies that are present, you move into
the phase 2, which is a risk assessment, where you
have OGTT performed, a normal glucose tolerance test,
a hemoglobin A1C. Some patients will have an
intravenous glucose tolerance test and some blood stored
for HLA typing, etc. Phase three is for patients that
have normal metabolic testing, but want to continue to be
followed up very closely. Again, hopefully, we'll identify
our patients before they develop DKA and prevent episodes of
DKA, so we want to keep a really close eye on them.
And most importantly is that offering the opportunities
for prevention studies, and which is the next
study that I'll talk about. So the next study, which is the
oral insulin trial, is really looking at trying to prevent
diabetes from occurring in high-risk individuals who
already have evidence from autoimmunity.
So this kind of comes back. This study is really built off
of the diabetes prevention trial one, and the DPT1, what
it's job was, or what the goal of that trial was, was to enroll
first- and second-degree relatives of patients
with Type 1. The average age is about 11,
so there were a lot of young children in this study,
as well as adolescents. And they were all screened
for autoantibodies. And individuals who had
autoantibodies were eligible, and they went into
one of two arms. They either received insulin
by subcutaneously daily, as well as intravenous insulin
once a year. Or they were in a close
observation group, which was the control group.
The second arm was an oral insulin or a placebo group.
Now the oral insulin does not metabolically active, but the
thought was that, again, it may induce a state of immune
tolerance and change or modulate the immune system.
So the hypothesis here is that we might be able to rest the
remaining beta cells by giving subcutaneous insulin, or change
or modulate the immune system to prevent further destruction
of the beta cells in the oral insulin group.
And unfortunately, what we learned is that neither arm
of this study did anything, actually.
So there was no difference over time in either of the
patients that received subcutaneous insulin,
or insulin about the development of Type 1 Diabetes.
However, as often happens in clinical research, it provided
a spark for an additional trial. And that really came from this
Post Hoc analysis, which is, obviously you don't want
to base your findings on a Post Hoc analysis, but it did
at least provide a stimulus for thinking about designing
a new intervention study. The Post Hoc analysis showed
that there did look like there was a benefit in patients
that were in the oral insulin trial who had very high titers
of autoantibodies against insulin.
Now these patients actually had antibody levels that were
above 80-90 units per ml. They were initially the group
that was targeted for this study, but because they wanted
to try to improve enrollment, they allowed some other patients
with lower levels of antibodies into the study.
But when they separated this group out, what they saw
that there was a projected five year delay in patients
who had high levels of insulin autoantibodies
who received oral insulin compared to the control group.
So the oral insulin studies really built off of this
Post Hoc analysis in looking at these patients, and asking
the question, well what about if we just target this specific
group who have high levels of insulin autoantibodies,
and give them oral insulin. Can we delay the development
of diabetes in this group? And the concept behind that,
and I see Dr. Lamansky in there, so I have to be really careful
about talking about all of this immune stuff.
The concept behind this is that this oral antigen or repeated
exposure of the oral antigen that is seen by the lymphocytes
here, will in fact, induce a state of immune tolerance.
So you have these lymphocytes here that see these proteins
from the oral insulin that are broken down.
They do not recognize this as a foreign protein anymore, and
they are sort of reprogrammed to circulate in the system and
are programmed to interact with these autoimmune cells, or these
cytotoxic cells that are present in the pancreas and the islets,
and telling these cells to actually induce a state
of tolerance, decreasing the inflammation in the pancreas
that's currently going on and inhibiting further
beta cell autoimmunity and destruction.
So who's eligible for this study?
These, again, are high-risk family members between the age
of three and 45, if you're a first degree.
Or between the ages of 3 and 20 if your a second-degree
family member. You have to have elevated
insulin autoantibodies with one other autoantibody
within the past six months. And you can't have evidence for
metabolic compromise on that. Okay, so moving on to the next
study, which is looking at again, a little different
population. And this study, which is called
the NIP Study, is looking really at modifying the immune
response in children that are at risk, before evidence
for autoimmunity occurs. And I was thinking that a good
segue into this study was letting you know about my new
adventures, as a Minnesotan and ice fishing experiences.
And this is a northern that I caught a few weeks ago.
It's the first one that I've ever caught.
And I was thinking this is a nice segue.
Number one, I can show off my fish.
And number two, was this northern pike here, although
it doesn't have extremely high levels, it does have
relatively good levels of DHA, which many fish sources have.
And DHA is an intervention study that we're actually looking at
for these high risk infants. That's what the NIP study is.
So the NIP study is basically looking at whether DHA, which is
an Omega-3 polyunsaturated fatty acid, whether
supplementation with that at high doses will block the
initial pro-inflammatory events, and prevent development of
autoimmunity in children that are high risk.
So these are really targeting infants, before the age
of six months. And the background on DHA,
as I mentioned, it's a Omega-3 fatty acid.
It's rather ubiquitous in the body.
It's a very important component of cell membranes.
It's found in tissues throughout.
We know that it probably plays an important role in
neurocognitive development, visual development.
It's supplemented in almost all of the standard formulas now,
and there are measurable levels in breast milk as well.
When you look at what's happened with our diets over
the past 200 years, and this is perhaps one of the theories
behind maybe why the incidence of Type 1 is starting to
increase a little bit. If you look at our diets
over the past years, and the ratio of Omega-6 fatty acids
to Omega-3 fatty acids. Back in the 1800s, it was close
to about a 1:1 ratio. And as things have progressed
and our food sources have changed, that ratio has changed
pretty dramatically now to somewhere in the neighborhood
of 20:1 or 30:1 of Omega-6 to Omega-3.
And why we think this may be important is that the Omega-3
fatty acids have many beneficial effects.
It's actually part of many cardiovascular disease
prevention programs, or for patients that have early
coronary artery disease, they're on Omega-3 fatty acids, because
they have an inflammatory effect, they have beneficial
effects on lipid panels. They are antithrombotic, and
they have a vasodilatory effect. And Omega-6 fatty acids
do the opposite thing. They're all derivatives of
arachidonic acid, which lead to a lot of inflammatory mediators.
So some of the sources of Omega-3 fatty acids: canola oil,
soybean oil, which can be found in mayonnaise, not that,
you know, you don't want to take a lot of mayonnaise in.
Varying sources of fish, salmon, canned tuna, flax seeds,
some leafy green vegetables, kale, and really interestingly
which I just found recently, Chia also is an important source
Omega-3, so if you really feel like you need some more,
you could always just go down to Walgreens and get a Chia Pet
and have some Chia that way. That was a joke.
( laughter ) So what's the evidence that
this might actually have a beneficial effect?
Well, right now it's been based off of initial studies which
have been done up in Norway, where the incidence of Type 1
Diabetes is even greater than what we see here
in the United States. And there are a few studies
that came out of there over the past 20 years that have
at least spurned this concept or this idea.
First, was that infants that were born to moms who lived in
fishing villages, compared to moms that lived centrally,
away from the coast, those infants actually had a lower
risk of developing diabetes than the infants that were born
more centrally. So the concept was that these
people are eating more fish and that may have an effect.
So not a lot of data there, but maybe an inkling.
And they followed up this study by looking at cod liver oil
supplementation, which is what they used for Vitamin D
supplements. And so, cod liver oil is a very
important source of Vitamin D. It also is an important source
of Omega-3 fatty acids. They found that pregnant moms
who were supplemented in this small county in Norway, that
their infants had a decreased risk, about a 63% reduction,
although just approaching the conference interval limits
there. And then they did a follow-up,
study looking more nationally, and although they did find that
infants who took cod liver oil during their first year,
they also had a reduced risk of Type 1 Diabetes, again.
Very borderline on significance, but they also found in the study
that there was no effect in the moms when they repeated this
study. So there was some evidence there
but it wasn't really great evidence.
At least, maybe it provided a clue that something
was happening there. More recently, and I think
which provided more fodder for our study is this DAISY study,
which is again looking at high risk children.
These are all infants that are born in Denver.
This is where the study is. And in this study, they're
actually giving the parents food questionnaires that they fill
out so they actually know sort of what their intake of
different food sources, how much Omega-3 they're taking in.
They had a separate group, where they're actually monitoring
red blood cell membrane DHA content.
And they followed these children for about 6.2 years, and then
they recently just published their data in JAMA, so it's just
a couple of months ago. And what they found was that
when you look at risks of developing evidence for
autoimmunity for these antibodies, and how that's
associated with dietary intake of Omega-3,
polyunsaturated fatty acids. That there is a reduction in
the risk of autoimmunity with increased intake of Omega-3
fatty acids by about 55%, and that association goes up
even greater. It's a stronger association
when you look at children that developed more than one
autoantibody. That was down to 70%
with a stronger P value. Now this was just for the food
questionnaire. And when they looked at that
cohort that they're following, just for red blood cell
membrane content, they found that same trend.
So if you look at the DHA content in the red blood cell
membranes, you see that same association between higher
levels of DHA and a reduction in the evidence of autoimmunity.
So this was very exciting. And I think provided more steam
and more enthusiasm for the NIP study.
So this was really a randomized double-blinded
placebo controlled trial, looking at DHA versus placebo.
There's two entry points. One is for pregnant mothers
in their third trimester who are carrying a high risk infant.
That means that they themselves have to have Type 1, or the
father of the child has to be Type 1, or they have another
child with Type 1. They're randomized to 800mg
of DHA or a placebo. And once the baby is born,
if the baby is eligible, which I'll talk about in a second,
the mom, if she's nursing, would continue on her study
of capsule. Or if she's not going to nurse,
then we actually provide study formula for those infants
that either have a standard amount of DHA or a study amount
of DHA in it. And the high risk infants,
again, to be a high risk infant, you can't have one of
the protective alleles that I mentioned before.
You have to have either DR3 or DR4 positive.
Or, if you have another sibling with Type 1 diabetes, you would
also be eligible. So those are the two entry
points, both moms in the third trimester and infants before
the age of six months. The objectives of this study,
which is in a pilot phase right now, are to actually
demonstrate that we can detect higher levels of DHA in the
red blood cell membranes of infants that are on study drug,
as well as a reduction of some of the inflammatory mediators
that are typically associated with autoimmunity.
Eventually, as we launch into a full scale trial, we'll be
again, reduction in appearance of autoantibodies.
So over the last six or seven minutes here.
I'm going to talk about some of the intervention studies that we
have for new onset patients, so the goal of these studies
is really to try to preserve the remaining beta cell function
and the remaining beta cell population in newly diagnosed
patients. Not only to do that, but also
to induce a state of immune tolerance for those patients,
so that there is not ongoing autoimmunity,
and ongoing inflammation and ongoing destruction
of beta cells. Again, we're really trying to
balance off the immune response so in patients that have
autoimmune disease, they have a tip toward more of
a TH1 response. Some of the these more
inflammatory destructive cytokines, like interferon
gamma, IL-1, IL-2 beta, and tip that more toward IL-2,
IL-3 response, which incurs some more of the protective
cytokines. So two studies that we've
already finished off, the first one was actually targeting
T cell mediated autoimmunity. This was using Daclizumab and
MMF that target the T cell population, specifically
Daclizumab inhibits IL-2 stimulation of the T cell by
binding of the alpha receptor of IL-2.
And then MMF, which inhibits the salvage pathway of purine
synthesis, As you all know, there are
many patients in the transplant population on MMF.
It's sort of a mild or immunosuppressive that kind of
keeps the immune system in check.
The second study was actually targeting those B cells, which
we now know are important. Using Rituximab or Anti CD20 to
deplete the B cell population. So again, here's how Daclizumab
works. It binds to this sub-unit of
IL-2 receptor on T cells and inhibits their activation,
via IL-2. There also is evidence that
some of these auto-reactive T cells go through apoptosis
without stimulation of IL-2, so we're hoping that go this is
going to be an effective intervention strategy.
So there are three arms of the MMF, DZB trial.
The three arms include active MMF and DZB.
The second arm is active MMF and placebo DZB.
And the third arm is placebo for both of those agents.
And again, if effective, we're trying to see if it
preserves beta cell function. And we do that using
mixed meal tolerance tests and looking at C peptide responses
for these patients over time. So we enrolled over 120 patients
nationwide. We're hoping that we'll have
some two-year follow up data in January of 2009.
And I think we'll hear more about the results of that study
at that time. Anti CD20.
Again, what it does is it binds to CD20 on B cells and
mediates depletion of B cells. This is a very effective
treatment in Hodgkin's lymphoma. We think it may be effective
in Type 1 Diabetes, as well, because it has been effective
in other T cell mediated autoimmune diseases.
And in this study, patients got four IV doses of Rituximab
one week apart, or they got placebo.
There are some side effects with Rituximab as there are
with Daclizumab, specifically transfusion reactions and risks
for infection after the infusion, so they're monitored
very closely for these possibilities.
Again, primary outcome which is all these intervention studies
are looking at, are what's the C peptide response after you
give them a mixed meal. And there are 68 patients that
were enrolled, which was the target number and we'll
probably have data, at least one year data on this,
later this year. The current studies we have
are using another drug called Thymoglobulin, which you may
have encountered in your transplant population, or some
autoimmune processes like aplastic anemia.
And Thymoglobulin is basically purified globulin from rabbits
that were injected with human thymocytes.
So you can imagine that the serum that you get from the
rabbits are full of different antibodies against various
markers on T cells. And that's the idea, you get
antibodies against several different T cell membranes,
CD3, CD4, CD8, as well as HLA heavy chains.
When you give this back to patients, you get a really
profound reduction in T cell counts, so about 85-90%
reduction in T cell counts. There probably is also some
effect on B cells and how they actually proliferate, so it's a
very powerful immunosuppressive agent.
Now when the T cells come back, they do come back, and when they
come back, what happens is that over these two months that
they start repopulating and that the make-up or the
population of the cells appears to be different.
There's a higher percentage of CD8 positive regulatory cells,
which is a positive factor in transplant studies.
And we think that there are more regulatory cells that may
repopulate the immune system after Thymoglobulin.
So not only where we hoping to sort of knock the immune system
down a little bit, but repopulate it with cells
that may not again participate in that autoimmune reaction.
It has been used in several other autoimmune diseases
like aplastic anemia in transplant patients.
And it has been effective in some mouse models, as well,
but as I mentioned before, the mouse model doesn't always
translate to the human model. So that's why we're performing
this trial. Really, in the Type 1
population, there have been a few case reports, interestingly
over 20 years ago, that shows that it may actually be
beneficial, but we don't have long-term follow-up there.
So for this study, patients come into the DCRC.
They're hospitalized there for five days.
They get four courses of Thymo, a total dose of 6.5mg.
Thymoglobulin, for anyone that's actually used it, can be really
nasty infusion reactions, so you can have cytokine release
syndrome, or you can have later effects from serum sickness.
It is a very potent immunosuppressive agent
and there are side effects. That's why they're monitored
in the hospital while we're giving it.
Again we're looking for C peptide levels
one and two years out. They only centers that are doing
it now is UCSF, which is where Steve Gittleman is,
who is the author of this study. They've enrolled two patients,
we've enrolled one patient so far.
We're really targeting older patients right now.
Down to the age of 18. They have to have diabetes
within 55 days of being enrolled, have one evidence of
autoantibody, and have evidence for endogenous production
of insulin still. So in that sort of honeymoon
phase that when that develops within the first week
or two after diagnosis. They have to be EBV Seronegative
and their randomized two to one to Thymoglobulin
versus placebo. They do get methylpred prior
to their infusion or placebo steroids, again, to try to
decrease some of the reactions that are going on.
And they're followed for 24 months.
Then lastly, is an intervention study using CTLA-4.
Now CTLA-4 is a really important inhibitory signal that's
typically expressed on T cells. So when there is a reaction,
when there is inflammation, when there is autoimmunity,
CTLA-4 comes out and is expressed probably about
24-48 hours later. We think that in Type 1
patients, there maybe decreased expression of this protein
on the T cell. So the concept or goal would be
by giving actually CTLA-4 immunoglobulin, we may actually
be able to, again, induce a more regulatory state and decrease
this autoimmune reaction. And how it works is on the
B cells, which function as the presenting cell here, this
interaction with both CD80 and CD86, they normally interact
with CD28, which induces this activation of the T cell
to participate in inflammation autoimmune response.
CTLA-4 is a negative protein, so by giving CTLA-4, we block
this response that occurs, this co-stimulatory signaling
that occurs here and it also probably has effects at
the T cell receptor and the MHC complex of the B cell.
So we think it blocks the stimulatory cascade.
It decreases the amount of IL-2 that's then produced.
And it probably has effect on self-cycle progression as well.
Again, some pretty good evidence in mouse models that
this is going to be effective, so if you make knock-out mice
that do not have CTLA-4, they get this really profound
lymphocyte proliferation, multi-organ destruction, and
lymphocytes just kind of go haywire.
And if you give these mice CTLA-4 immunoglobulin,
you can actually prevent this from occurring.
CTLA-4 appears to inhibit release of TH1 cytokines, but it
doesn't inhibit TH2 cytokines. And this is in a model
of autoimmune encephalomyelitis. It has been shown to be very
beneficial in a number of transplant models, as well as
in prevention of autoimmune diabetes in the NOD mouse.
It's trade name is Abatacept, so it's a commonly used agent
in children with rheumatoid arthritis,
multiple sclerosis, psoriasis, and it's also being used in
a number of other trials for autoimmune disease.
So this study goes down to younger kids, because it is
better tolerated. It doesn't have the same kind
of reactions. The rest of the inclusion
criteria is very similar. It's, again, two to one
intervention, and we're looking at targeting 108 patients.
There are some risks for infections, but they're not
quite as profound as Thymo. And that's just getting off
the ground right now. So in the future, where I think
things are going both in TrialNet and in other branches
of research and clinical diabetes work.
Well, there are probably going to be more immunomodulatory
regimens, such as using Anti-CD3, plus the addition
of exendatide, which is a peptide 1 antagonist, that
preliminary data shows that it may actually help promote
proliferation of beta cell repopulation, or increase
the number of beta cells. There are vaccinations coming
down the pipe using glutamic acid decarboxylase, again, as
a way to induce immune tolerance in patients that have evidence
for autoimmunity. And what we'll probably do here
through John Wagner's lab at University of Minnesota is
trying to enhance that T cell regulatory population, that you
can pick out of the peripheral blood population,
enhance that population, give it back to patients.
And then for patients with long-standing diabetes,
we've got islet transplants, which are getting better,
but aren't quite where we want them to be.
Xenografts using pig islets, which is coming down the pipe.
There's been evidence from Dr. Bernard Herings' group from
the University of Minnesota, showing that they can actually
do that in primates, and transplant islets from pigs
into primates. Stem cell transplants.
There's one study that came out in JAMA last year about an
initial study of a small group of patients that shows a lot
of promise there. And then also just improved
insulin delivery systems. So we're looking toward closing
that loop of insulin delivery and glucose monitoring.
So just to review, the studies that we have out right now,
genetically at risk we've got the NIP study we're
using Omega-3 fatty acids, Humoral autoimmunity,
oral insulin, so people who have evidence of autoimmunity,
using oral insulin, that group. New onset patients,
Thymoglobulin, CTLA-4, which are currently there and then
trying to increase our knowledge of what's going on from
a natural history standpoint through Type 1 diabetes
Genetics Consortium, as well as the natural history study.
I think this is Billy Leroy, who is one of the first patients
to get insulin. And you can just sort of see
how wasted he was here prior to getting any insulin.
This was really the only treatment before we had insulin
was actually starvation. He gets put on insulin and
you can see the really dramatic results, so this is really
life changes for patients with Type 1.
And I think we're approaching that next phase of really
changing the course of diabetes with some of the trials
that we're doing, and some other trials that are going on
elsewhere. And it's a little cheesy,
but I do miss the UW Band. And I really feel like we are
kind of marching toward a cure here.
So hopefully, we'll see that happen all in our lifetimes.
I just wanted to acknowledge everyone from the university,
allowing me to skip clinic today and come down to be able
to talk to you about some of our studies.
We have a great group that we work with, and really appreciate
your attention and the invitation
to come down today. So thank you.
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