World Conference--New Research

World Conference--New Research

WORLD DIABETES
CONFERENCE REVEALS NEW RESEARCH

by Ed
Bryant

On March 19, 1997, the Juvenile Diabetes
Foundation International (JDFI) sponsored a unique event; an international teleconference
press-briefing with some of the world's leading diabetes researchers. Held at
the close of the JDFI's Fourth World Conference, in Athens, Greece, it brought
together 140 specialists in all aspects of diabetes research, with the hope
that their sharing and networking might advance the cause.
Several researchers gave short presentations,
and then the session was opened to questions from members of the press. I was
fortunate to be invited to participate in this event. The researchers were linked
from different places (one was calling by cell-phone from an airport!), and
the reporters were all linked to them, from our different locations, through
the conference operator. It was quite an experience.
First, Philippe Halban, PhD (University
of Geneva, Switzerland), Scientific Co-Chair of the Conference, outlined the
areas covered by the Athens Conference. As he reported, sessions were organized
along five tracks: Insulin action and resistance; Pancreatic Beta cell growth,
differentiation, and death; Ramifications of diabetes; New methods of treatment,
new ways to administer, and new ways to monitor, and; Immunology and islet cell
transplantation. Participants, involved in different aspects of research toward
prevention, treatment, or cure of diabetes, were encouraged to interact, and
to become more interdisciplinary.
The next speaker was Arthur Rubenstein,
MD, from the University of Chicago. He is an expert on trends and statistics
of diabetes, and, as he stated, much of that information is not readily appreciated.
"It's importance should be recognized by all of us who are thinking about
the impact of chronic disease on the health care system," he told us.
He revealed how there is tremendous
variation in IDDM occurrence world-wide, with some countries, like Finland,
having as many as 35 occurrences per 100,000 individuals, while others, like
China, have as low as 1 per 100,000, and the U.S.A. is closer to the middle,
with 5 to 10 per 100,000 individuals. He stated that type I diabetes is the
most common chronic disease of childhood, more common that all childhood cancers
combined.
He discussed the genetic connection,
and the fact that chances of developing type I diabetes are much higher (up
to 5 per 100 individuals) in a family with an affected parent or sibling. "IDDM
is becoming more common," he reported, "with quite a dramatic increase
in the last 30 years, even increasing in the last 10 or 20 years."
Dr. Rubenstein related some of the changes
that had taken place since the last JDFI conference, in 1992. Through changes
in genetics, we know far more about who is at risk. Our better immunological
understanding of antibodies and autoimmune disease process enables, for the
first time, diabetes prevention studies, which are currently underway in the
U.S., Europe, and Australia.
We have new techniques to identify who
is at risk, even before diagnosis, and, since the publication of the Diabetes
Control and Complications Trial, in 1993, we have a new approach to the treatment
of diabetic complications, one that in 1992 was not even considered possible,
he reported. Dr. Rubenstein mentioned ACE inhibitors, "growth factors,"
anti-neuropathy drugs, new developments in transplantation, and cell engineering.
New insulin preparations and oral drugs are under analysis, and may prove useful.
Many important avenues of inquiry, for both basic science and patient-oriented
care, are currently being followed. This, he stated, should lead to rapid advances.

The next presenter was Leonard C. Harrison,
MD, Professor, head of the Burnet Clinical Research Unit, University of Melbourne,
Australia. He spoke on the autoimmune nature of type I diabetes and its onset.
With, in his words, "the explosive increase in this knowledge in the last
decade or so," and the recognition that this disease is due to the interaction
of many genes that act together to predispose an individual, placing them at
risk, it may be possible to protect against the disease through genetic analysis.
Dr. Harrison reported on our vastly
improved understanding of the role of T-cells. Although, as he stated, we still
do not know what triggers this destructive autoimmune response (the killing
the Beta cells of the pancreas that causes type I diabetes), it is now known
how the T-cells find their targets, the specific peptides they single out for
attack. Thus, he hoped, we might someday be able to intervene and subvert this
process.
Dr. Harrison's research has revealed
that the prime target of the rogue T-cell attack that causes type I diabetes
is insulin itself, or more specifically proinsulin, its parent compound. With
his research, he hopes to intervene in people at risk, modifying the immune
response before the T-cells can destroy the Beta cells and the pancreas' insulin-making
ability, causing type I diabetes.
The mucous membranes in the nasal cavity
are now known to have their own separate "immune system," primarily
to prevent or restrict inappropriate immune response to proteins inhaled or
ingested. Dr. Harrison's research team has been administering insulin and proinsulin
orally and intranasally to mice, then to humans, not for blood sugar control
but to ameliorate T-cell attack, in a type of "vaccination" designed
to create immunity from such T-cell attack.
Aerosol administration of insulin in
mice cut their frequency of type I diabetes from 90% to 25%. A new human trial,
in children and young adults already at high risk (who show antibodies and T-cell
attack, with more than 50% chance of developing diabetes) started July 1996.
(By the way, aerosol administration of insulin to regulate blood glucose was
tested several years ago--it failed.) The goal of the research trial is to determine
whether this treatment, effective in mice, will work in humans. By the end of
1998, the first stage will be completed, and if successful, research will proceed
to investigating the possibility of prevention.
John Todd, PhD, Professor of Human Genetics,
Oxford University, spoke of new understanding of the gene defects that predispose
an individual to type I diabetes. Using the database called "The Human
Genome Project," he reported we can now identify the specific genes, and
the nature of their defect or malfunction.
Professor Todd related two specific
examples. The first and most important is an "immune response gene,"
that normally controls identification/differentiation between "friend"
and "enemy" particles in the human body, leaving one unharmed and
summoning killer T-cells to destroy the other. Normally this gene plays a positive
role, but it is the gatekeeper, controlling the identification of the Beta cells
as friendly or as something to be destroyed by immune action. What causes this
important gene to turn traitor? Once known, can this knowledge be used to identify
those at higher risk?
Dr. Todd revealed that the human pancreas
is not the only source of insulin; the hormone is also produced in the thymus
gland. Significantly, the thymus is also the organ that prevents autoimmunity.
One gene in a healthy thymus protects against the onset of type I diabetes.
If a second gene goes defective, and attacks the first, diabetes will result.

Another study Dr. Todd related concerns
Interleukin-2, the T-cell growth factor. This substance's main function is to
prevent autoimmunity; in autoimmune-prone individuals, it is reduced. There
is possibility that a test for this defect, reduced levels of Interleukin-2,
could reveal incipient diabetes. "There must be at least 10 other susceptibility
genes that remain to be discovered," he stated.
Dr. Todd related that the autoimmune
process by which the body attacks and destroys the Beta cells of the pancreas,
causing type I diabetes, is identical to the process by which the body rejects
a transplanted organ. As our understanding of the one process grows, we should
be better able to deal with the other.
Emily Spitzer, the Juvenile Diabetes
Foundation's Vice President of Research, then made a short presentation about
the need to press on for a cure, and to "move basic advances closer to
the patient." She reiterated the goals of the JDF, which in 1996 awarded
more than $30.3 million to diabetes research, and which has given $220 million
for such research since 1970. She reminded listeners that people are "not
at fault," if they develop diabetes, or its complications. She then introduced
the "Q & A section," in which members of the press could, through
the special conference-call hookup, ask questions of specific presenters.
Although any "question-and-answer
session" is by definition random and unstructured, subjects covered here
continued to hold listener interest. A question about nasal-spray (aerosol)
administration of insulin (or proinsulin) revealed that such administration
can protect against autoimmune attack and the development of insulin-dependent
diabetes mellitus (IDDM, type I diabetes) even after the autoimmune attack has
begun. It seems there are "regulatory T-cells," as well, and these,
if properly directed, protect against attack.
Of course the question came up: "How
close are we to a cure?" The responders pointed out that there are a number
of meanings to the word "cure," and that pancreas transplantation,
which eliminates the need for insulin or oral medications, could be described
as a cure for diabetes. Islet cell transplantation, to reestablish insulin-making
capacity in the diabetic pancreas, is in the experimental stage. Sometimes it
works. As the problems are worked out, look for real progress in this area.

Part of the difficulty with transplantation,
either to mitigate diabetes ramifications or for other conditions, is the problem
of immunosuppression. At this time, a transplant recipient must take heavy doses
of immunosuppressive drugs, to keep his or her immune system from destroying
the new organ (in exactly the same way the diabetic autoimmune system destroys
islet cells). Safer, more specific ways to prevent transplant rejection are
needed.
There is a lot of research underway
in the area of nerve fiber growth and regeneration. Up to this time, although
damaged nerve fibers might heal, if destroyed, they would not regenerate. If
we can stimulate damaged nerves to better "repair" themselves, we
can reduce many of the ramifications of diabetes.
The doctors argue that no "cure"
for diabetes can take place without the achievement of reliable diabetes prevention.
When individuals in the early stages of diabetes can be treated with something
that stops the disease in its tracks, and when individuals considered at high
risk can be "vaccinated," so that diabetes never starts, then we will
have a real "cure."
The subjects covered in this unique
international press conference were promising, even exciting. While we work
day-to-day to perfect our self-management techniques, keep the best possible
blood glucose control, and thus minimize our risk of ramifications, world-class
researchers are pressing on with the search for breakthroughs that will make
it all unnecessary. The search for a cure goes on--and some good folks are on
the job. May it come soon.