January 10, 2005
A: FROM MENTOR MINI VARUGHESE IN MD
First link is for Gene Therapy.
http://cis.nci.nih.gov/fact/7_18.htm

This link is about diabetes and how the different medications work and
different treatment options under test.
http://diabetes.niddk.nih.gov/
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January 3, 2005
A: FROM MENTOR LEE PELLEGRINO-GENSEY IN NJ
Kunjal, I can answer your question about adding the insulin gene back into
pancreas cells, but I don't have much background on your other questions.
The internet can probably provide you with some of that - look up a
newsletter called the "Insulin-Free Times" for example. In type I or
juvenile diabetes, the cells in the pancreas that produce insulin have been
destroyed by the body's immune system, which mistakenly thinks they are
foreign and harmful. However, there are several different kinds of cells in
the pancreas and getting the right ones replaced is tricky. Most of the
pancreas is dedicated to producing digestive enzymes, and these cells are
called "exocrine" cells. A very small part of the whole cell population
forms the "islets", which contain 4 kinds of cells (alpha, beta, delta, and
PP) which produce insulin and other enzymes in response to glucose and other
signals - these are the "endocrine" cells. Only the beta cells in the
islets have been destroyed by the body. The beta cells are very specialized
- they have a certain set of genes turned on and functioning which is
different from the genes functioning in the other islet cells or the
exocrine cells, so it's not a simple matter to take any of the surviving
cells and simply put in an insulin gene. You might be able to get them to
make insulin all the time at a certain level, but you would not have the
normal response to glucose, in which insulin is produced in just the right
amount to deal with the glucose in your bloodstream at any given time. You
also have to include the glucose-sensing and insulin-releasing mechanisms to
have good replacements.

There are many groups around the world working on doing exactly what you
suggest (creating insulin-producing cells to put back into the body). The
closest thing currently in clinical use is to transplant islets taken from
the pancreas of organ donors, but not all of the islets survive the process
of being isolated from the pancreas, and since the pancreas is from another
person the recipient must take immune-suppressing drugs for life to prevent
rejection, and some of those drugs are harmful to islets! Most of those
patients require up to four transplants to achieve insulin independence,
which does not seem to be permanent (look up "islet transplant" on the
internet). Much research is being done to find a cell source that can take
starting material from the patient's own body (thus not needing
anti-rejection drugs), from a donated organ, or even from animals, and
persuade those cells to take on the characteristics of beta cells. Others
are working to find anti-rejection drugs that won't be toxic to the
transplanted cells and to find ways of packaging the cells to make a
mini-organ for transplant.

Each cell in the body is already committed to expressing a certain set of
genes for its function - a liver cell is different from a bone cell or a
skin cell - and those committed cells aren't likely to change their set of
expressed genes, even the other populations of cells from the pancreas.
Many researchers are therefore looking at stem cells as a source - for each
organ or tissue there is a tiny population of cells that have not yet
committed to any one cell type - for example, liver stem cells can
regenerate any of the many types of cells in the liver. Can you take a
liver stem cell and give it the right signals to get it to express pancreas
genes? Can you find a pancreatic stem cell and give it just the right
signals (and of course no one knows what these are yet) to make beta cells?
Do you need to go to embryonic stem cells, which are capable of becoming any
cell of the body, but are controversial? Can you do it repeatably and
safely in the necessary quantities? Will the body continue to reject and
destroy these new insulin-producing cells just like it did the original
ones? Can you keep transplanted cells alive in their new location long
enough for new blood vessels to grow to them and provide oxygen and
nutrients?

The questions are many and the work is complicated, but I see progress in
this field and I am proud to be part of it. I hope we can all see this
happen in our lifetimes. Keep asking questions - this is how progress is
made.
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A: FROM MENTOR LESLIE WAITE IN CA
Hi Kunjal!
What a great question! I study a protein involved in glucose (sugar)
regulation, and drugs that activate the protein that I study are used
to treat type II diabetes (see below), so this is a subject near and
dear to my heart.

Your idea of injecting the insulin gene into pancreatic cells is a
really good one. In fact, scientists are working on something very
similar to what you suggest, with a few modifications.

First, a bit of clarification on diabetes and sugar metabolism. In
most folks, when we eat, we either eat things that contain sugar
(specifically glucose), or things that get converted into glucose
after we eat them. In someone whose system is working properly, the
presence of glucose in the blood generates a signal that tells the
beta cells of the pancreas to make insulin. This insulin is secreted
into the bloodstream, and helps your body to metabolize glucose
properly. Only beta cells make insulin; other pancreas cells can't do
it.

There are two kinds of diabetes, type I and type II. Type I is the
kind you usually get when you are young; most diabetic children are
type I diabetics. In type I diabetes, the beta cells of the pancreas
die off for reasons that we don't understand. They are destroyed by
the body in what is called an autoimmune response. Auto means "self",
so an autoimmune response is an immune response that incorrectly
attacks your own cells that are OK instead of disease-causing
bacterial cells or viruses. Other autoimmune diseases you may have
heard of are lupus, multiple sclerosis and some types of muscular
dystrophy, just to name a few. But back to diabetes: In type I
diabetes, the cells that make insulin are destroyed, so there is
simply not a way to inject the insulin gene into them: they are gone.
Therefore, type I diabetics must have insulin delivered to their
bloodstream. However, there are some studies underway to try to
replace the lost beta cells in these individuals with healthy beta
cells. So instead of injecting insullin into beta cells like you
suggest, scientists are trying to inject the beta cells themselves
into the pancreas of patients with type I diabetes. This is still in
a test stage. So far, it seems the cells work OK for a short time,
then they too become victims to the same autoimmune response that
destroyed their original beta cells. Some folks are also hoping that
we might be able to use stem cells to make beta cells, since stem
cells might not evoke an autoimmune response. In any case, we need to
learn a lot more about the autoimmune response that destroys beta
cells before we can really make this work.

Type II diabetes is the kind people generally get when they are
older. It is also starting to show up in younger folks who are fat.
We now know that fat cells are involved in the process of regulation
of glucose, and having too much fat tissue can throw things off
kilter. In type II diabetes, the problem is usually not that you
don't make insulin, but that your body doesn't respond to it
normally. This is what we call insulin resistance. Because of the
nature of Type II diabetes, being able to make more insulin
frequently won't help.

As for other ways to give insulin to type I diabetics, the best
method we have so far is injection. This gets insulin in a usable
form directly into the blood stream. One other method that is
currently under investigation is inhaled insulin. This method would
allow diabetics to use an inhaler much like the ones you see folks
use for asthma. While some studies show this is a promising way to
treat diabetes, there are still some problems with it, namely that
much of the insulin you inhale doesn't make it to the blood stream,
but is destroyed by proteins in the lungs first. Similarly, pills
containing insulin are destroyed in the stomach during normal
digestion, so I don't really know of any options to get insulin from
pills at this time.
There are pills that you can take for type II diabetes, but these are
not insulin pills. These pills help stimulate your body's sensitivity
to insulin, so that it uses the insulin it has more effectively. One
of these pills (Avandia) is a drug that stimulates the protein I
study, which helps the body be more sensitive to insulin.

For more information on diabetes treatment and alternatives to
insulin injections, go to the American Diabetes Association's web
site:
http://www.diabetes.org/for-parents-and-kids/diabetes-care/insulin-medications.jsp

Then look at the different links on the page, especially "alternate
insulin delivery systems".

Good luck!
Leslie