A cure for type 1 diabetes!

Prof Eli Lewis

on a medical holy grail
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Dr Eli Lewis, professor of clinical biochemistry and pharmacology at Ben Gurion

University of the Negev, a public research university in Beersheba, Israel, may have
stumbled across one of modern medicines most enduring holy grails: a safe, effective
way to reverse type 1 diabetes. Lewiss research focuses on the tissue damage that
plays a role in type 1 diabetes, and which he says is often overlooked and under-
studied. Back in 2003, Lewis began researching the role of inflammation in injured
islets tiny clusters of insulin-producing cells in the pancreas and the effects
of transfusions of an anti-inflammatory drug based on a protein the body produces
naturally all the time, known as Alpha 1 Antitrypsin (AAT, or alpha1). AAT has so
far been used mostly only to treat emphysema, but Lewiss breakthrough research
shows the proteins promise via transfusion in reducing insulin dependence in type 1
diabetics, and in some cases actually reversing the condition completely, if caught
early enough. He believes it may help type 2 diabetes, again if the disease is caught
early enough, and supported with lifestyle change, including keeping carbohydrates
low, which he says is essential for diabetics.

Lewis describes AAT as a form of immuno-modulation, and says its application

goes beyond diabetes: US researchers are currently studying inflammatory bowel
disease in patients; bone-marrow transplant prognosis is phenomenal with AAT
according to a Seattle trial; researchers are testing it in ischemic heart disease for
diminished cardiac scar size; and it shows promise in multiple sclerosis (MS).
Other diseases in the pipeline for testing include lupus and rheumatoid arthritis,
transplants of all kinds and even pig-to-human grafting experiments that are
starving for a safe therapeutic to accommodate the grafts. Since his group is focused
on the immune assault on cells, Lewis says they are limited in funding and scope, and
are reaching out to collaborate with any group, as long as it is as enthusiastic as we
are. Here Lewis explains how the therapy works for type 1 diabetes. Marika Sboros

My guest today is Dr Eli Lewis, professor of clinical biochemistry and

pharmacology at Ben Gurion University of the Negev in Israel. He is in the
universitys clinical islet lab that is part of the universitys department of health
sciences. Dr Lewis is a medical scientist who could be bringing the world closer
to a cure for type 1 diabetes.

Dr Lewis, first of all tell me whats a clinical islet?

A clinical islet is what you end up with when you have to name your lab in any
way thats relevant to your work,. I try to combine everything to we do into one
title. So Islets are these little tiny spheres that you have in your pancreas making
insulin.

I remember in biology at school learning about islets of Langerhans?

Those are the ones. Every person has in his or her pancreas one million of these
spheres, one million islets. In them, most of the cells are beta cells that make
insulin. Its the only hormone that is able to lower glucose in the blood, the only
cells that make it, and its the only location where they are placed.

So its a very dangerous entity when you consider that if you lose the beta cells
for any reason, glucose will rise in the blood. It will just rise in the blood, thats
how it goes, no way to pull it down, theres no other hormone.

Are we talking now about type 1 diabetes?

The state of art today is changing: Type 1 diabetes has been renamed type 1
auto immune diabetes to be more precise. It is an auto immune condition, you
literally see int he blood circulating antibodies against the islets, against insulin.
So its an auto immune condition. It used to be called juvenile diabetes, but we
actually see it today also in adults and later on, patients engaging in with 1 auto
immune any time in life, so its no longer juvenile.

So you mean type 1 diabetes can be diagnosed at any age?

Different ages, in some cases, after 30 years. The trigger can be one of many. We
still dont know what no longer what instigates the actual condition, but its no
longer reserved only for kids.

In type 1 diabetes, the pancreas does not make any insulin at all?

That is what we call the end point of the disease, the point where the disease is
called end stage, as if there is no next step for it. You basically lose a mass of
viable cells.

For treatment, what patients have today, what caregivers have to offer is insulin.
Its basically that component thats missing in the blood circulating. The therapy
is roughly 100 years old. Unfortunately, since its discovery insulin in different
forms, although there are different ways of introduction in actually fascinating
technology advancements, it is still basically insulin. It is very difficult for us to
manually know how much insulin you need at every moment, but it is helping
the condition, it is treating the patients.

But what about the cells that have expired thats something that is not
addressed today. What my works is trying to do over the past 10 years is to do
deal not with with levels of insulin which can always be introduced, but with the
actual disease, the death of the islets or their absence or function. Those are
things Im trying to alter.

You are trying to do that with this new drug Alpha-1 antitrypsin (A1AT,
aka AAT or alpha 1) is it a drug? In your research you say its natural
compound that occurs in the body?
Precisely. Its a molecule, a protein. Everyone of us makes this protein, you and I

And people with Type 1 diabetes?

Actually yes, they also make it, but theres a point Ill get back to in a second. We
all make AAT in the bloodstream all the time. When we are sick, we make more
of it. What do I mean sick? If you have flu, an infection, you feel horrible,
inflamed, and the body makes more AAT in the blood. That has been known for
decades; people have been measuring it; doctors have used that level of higher
AAT as if it is a marker of whether or not there was an actual infection or
disease.

But if you study it deeply enough as I have done for past 10 years, it turns out it
actually has a function, and the body doesnt just release it and increase the
levels when we are sick. It does so on purpose appropriately so.

Its one of a series of molecules we use to protect our tissues. Why do we need
to protect our tissue when we are sick? Because the involvement of the immune
system in correcting an infection, in clearing or decontaminating it, is very
drastic. Our cells are very sensitive. The immune system has to use that platform
of innocent, sensitive tissue to destroy bacteria, viruses, fungi, parasites, cancer
cells, dead tissue

Its a very drastic event, and while it happens, you want it to execute its full
ability to decontaminate the area, but meanwhile the tissue suffers, actually
endures a lot of inflammation, injury. Its not the best way to go through illness.

At the point when AAT rises in the blood, it circulates in the body systemically, it
reaches everywhere; some tissues like the lungs and gut make the molecule
for their own sake. it helps to facilitate closing these micro wounds. It speeds up
the wound healing process. It is anti inflammatory, so it downplays
inflammation.
It allows inflammation to exist, but at a very low level. And when you are sick,
your body enjoys this extra protection around the areas that are experiencing
the immune event.

So what does this have to do with type 1 diabetes?

AAT has a very close relationship with diabetes. It turns out that circulating
glucose levels, when they are high, actually stick to proteins. Some of your
listeners may know about the measurement HbA1C Hb for haemoglobin, A for
adult, and 1C means it is coated with glucose. Its actually stuck to glucose.

Everything in the blood gets coated with glucose in diabetes, both type 1 and
type 2 diseases. When it is coated with glucose, even albumen gets coated with
glucose, everything you put in a glassful of glucose over time will be coated. You
dont need enzymes to do that.

For AAT, this means it becomes inactivated. It has been shown for the past
almost 20 years, that what levels of AAt the body makes becomes inactivated in
diabetics; its not functioning.

In clinical trials we have been running, trying to see if AAT infusion may alter the
disease, the first thing we found (with patients) was when they came in, they had
an inactive form of AAT.

The form of AAT you are giving type 1 diabetics via transfusion is it
natural or synthetic? It would have to be what you call exogenous?

Exogenous, but luckily it is purified from plasma. So we are basically introducing

the native molecule that is in the plasma.

Apparently the companies that work with blood products share I learnt this
recently 50 000 litres of plasma globally. They extract human albumen, human
anti bodies for medical purposes, and AAT enjoys this extraction. It is purified
and bottled up, and the reason they do that has nothing to do with diabetes.
We came very late with the concept we have (on AAT for type 1 diabetes), before
we knew about the advance (for its use) in another disease.

Which disease is that?

Its called A1AT deficiency. It has been with us for quite a while. Medical
textbooks will have half a page on it, showing that if you have less than normal
AAT genetically, it turns out that it is slightly mutated; instead of being produced
and released into the blood, it is just produced and stuck in the cells.

For those individuals, that doesnt change much until they develop lung
emphysema the breakdown of the lung walls; also they endure more
inflammatory bouts, vasculitis (inflammation of blood vessels), things like that ,
from having lower levels of AAT.

So AAT can be used to treat emphysema?

At present, thats almost the only indication. But we feel lucky because for the
past 30 years it has been bottled up on the shelf exactly for this rare condition
around one in 10 000 individuals roughly will be diagnosed with A1AT deficiency.
They are eligible for AAT infusions

For us, its wonderful, when you consider that we have a drug or regimen to give
to people, including children, maybe for life, men to give to kids, and who knows
maybe, for life, you are not sure. Ten years ago we decided to adhere completely
to testing on safety and feasibility on a drug that is identified already as usable
and clinically safe.

How long would it take to reverse type 1 diabetes using this drug?

We have a lot more experience now than we had before. At the time we started
testing AAT infusions in patients, it took a very long while to identify the window
of opportunity. We had no idea how long we would need to administer the
infusion. In pre-clinical studies, in the early years of intensive experiments in
animal studies, we discovered that it takes a few weeks at least for the immune
system to alter for the better. It cant be done overnight, or a week or two. It
needs four weeks at least in mice and rat models.

But if its animal studies, particularly in rodents, you cant generalise to

humans?

Oh, completely.

Will you be doing human trials soon?

Oh yes, the next trial is running already one at Ben Gurion University, two
others currently recruiting in the States; we have several teams in multi centre
working on it.

This is really revolutionary! Is your hypothesis that this will be a long-term

cure, or you dont know that at this stage?

We dont know exactly. The longest we have followed a patient that has been
treated for a while with AAT, is eight years. That is in a child who was for eight
weeks, and still has no need for insulin. He is still making his own after eight
weeks of infusions.

But that said, we still have to find the best window opportunity for each patient.
We are not sure. We are thinking that it is very close to that close to time of
diagnosis, so that really doesnt help those who are years down the line with the
disease.

All clinical trial will usually always recruit individuals who are soon after
diagnosis, as that it the dynamic point of the disease. One clinical study of 59
patients showed that all started to make their own insulin after receiving 37
weeks of A1AT, so it could be that the longer the better. But we never knew at
the time, so we could afford to try it for a few weeks and then stop.
But also, every type 1 diabetic is slightly different. It depends on at what age the
patient gets it, the age of onset, the patients background, level of antibodies
that goes up and down, other diseases that may be present. So we dont think
this will be a uniform, mass treatment. Type 1 diabetes is a disease that
deserves to be individualised.

Yes, personalised medicine is proving to be the way to go, and also I

presume, supported by lifestyle change?

That is always in the background one of things that I strongly support. I turn to
parents all the time, and say they have actually have a lot more information that
all the medical groups put together. When parents have a child who is type 1
diabetic and the years go by, they individually calibrate what s good for the kid,
whats not good for the kid, what aggravates the condition what fits well. They
know best.

There are no two kids who get the same diet, but the longer the parents follow
what works, the better they fit the diet to their kids, when the kids grow up they
follow this on their own. They are very responsible individuals, very aware of
themselves.

Do you have any thoughts on the role of carbohydrate in the diet for
diabetics?

Oh yes, completely! In diabetes, the pancreas in this disease is suffering an

attack, an assault; the pancreas is injured. These spherical entities, the islets are
actually destroyed by high levels of glucose; they are sensitive in ways that mean
they can actually expire if someone has a lot of glucose.

Carbohydrates consider them macromolecules of a lot of sugar actually load

a burden on anyone, but especially someone with type 1 diabetes.
Carbohydrates force the pancreas to work harder. I will never say something like
reduce (carbohydrates) to zero percent anything. We have never been designed
to survive on earth with diets that contain zero percent anything, just
moderation and common sense.

It make intuitive sense to keep carbohydrates down.

Can AAT treatment help type 2 diabetics as well?

Great point! First of all, you have to consider that what we sit upon here, this
molecule, and shedding light on a particular juncture in immunology, is not
necessarily completely restricted to type 1 diabetes. Thats because there is an
interface where inflammation, immune cells and suffering cells meet.
AAT disengages some of those vicious cycles that tend to aggravate themselves.

First of all we have to consider other immune conditions. There is some

evidence that AAT infusion can help to deviate the course of multiple sclerosis
(MS). Thats an exciting (avenue of research), as my mother suffered from MS. It
was from a pre-clinical study done between our group at Ben Gurion University
and (US scientists) in Portland. Can I take half a minute here to tell you what it
means to be a researcher?

Please do!

We shipped over shipped over those special animals that make human
antitrypsin to Portland for them to study MS, because thats their specialty. I
work on diabetes, they work on MS.

The first phone we got was two days after the beginning of the experiment and
they said: Its such a shame, we had so much invested in shipping the mice and
coordinating (the trial), but you should know they all got MS, they all entered the
disease just the same way as the others. That was disappointing, but you live
through it.

After two days they called again to say: Prof Lewis, they all recovered and the
other mice continued to get paralysis and died. I still get chills thinking about it
because of what the other mice did in this treatment the disease did have one
step forward to act, but having so much AAT, it regressed,

Thats what we actually think the body is doing when it normally makes more
AAT: its part of speeding up wound healing when there is an event.

Its really hard for me to give seminars to clinicians on this subject, especially,
there are no side effects to this molecule at the range we are considering, and at
the duration, definitely.

People until now have taken (AAT) for life and at higher doses. (For diabetes), we
mimic those doses and limit treatment for several weeks. Safety is no issue,
absolutely. In fact, even the FDA (Food and Drug Administration, the US
regulatory body) immediately approved phase 2 trials of AAT in patients. There
was no need for toxicology trials, because everyone knows if a healthy person
gets it, nothing bad happens.

Thats impressive, but clinicians find it hard to accept. It is hard to accept, I agree.
You would want to know what happens long-term, after many years. Well, these
patients have been followed for 13 years, 25 years on A1AT infusions. Thats vey
long-term for weekly infusions.

And we do know that if anything, patients have lower infection rates, and lower
cancer rates than normal populations. Because they are being treated all the
time with A1AT, their bodies are basically submerged in this mode where their
immune system is functioning but their tissues are protected. That mode is very
precious

So this is one of the holy grails of modern medicine a cure for diabetes,
but not only for type 1 diabetes, as it has many other applications?
You mention type 2 diabetes. When it is diagnosed, it is in many ways worse
than type 1, because the patient has probably had type 2 diabetes for more than
10 years.

Type 2 diabetes is heavily underdiagnosed, and goes undetected for a very long
time. Usually if you ask type 2 diabetics what happened that they were
diagnosed, it could have been a routine check up at work, and suddenly their
glucose levels were very high. All that time A1AT is neutralised, inactivated, hard
to control, in people whose lifestyle is pretty much fixed.