BOSTON -- Researchers at Beth Israel Deaconess Medical Center
(BIDMC) have found that a triple combination therapy consisting of both
tolerance-inducing and anti-inflammatory properties is successful in
abolishing adverse autoimmunity against insulin-producing cells in a
mouse model of Type 1 diabetes.
The findings, which appear in the Online Early Edition of the
Proceedings of the National Academy of Sciences (PNAS) this week, offer
a possible new prototype for therapies to restore normal blood glucose
levels in diabetes patients and suggest a previously unrecognized role
for inflammation in the disease.
“Type 1 diabetes is known to develop as a consequence of autoimmune
destruction of insulin-producing pancreatic beta cells,” explains
senior author Terry Strom, MD, Director of the Transplantation Research
Center at BIDMC and Professor of Medicine at Harvard Medical School.
“But in addition to the long-recognized role of T-cell-dependent
immune-system-mediated islet destruction, this work reveals for the
first time that a form of inflammation in fat and muscle [is also
acting to] prevent insulin from disposing blood glucose into tissues
that require glucose.”
Formerly known as juvenile-onset or insulin-dependent diabetes, Type 1
diabetes develops when the body’s immune cells attack and destroy its
own pancreatic beta cells. Without beta cells, the body is unable to
produce insulin, a hormone needed to convert glucose into energy. To
prevent the development of serious complications, more than 21 million
individuals with Type 1 diabetes – primarily children and young adults
– must receive as many as three injections of insulin each day.
Previous attempts to treat existing Type 1 diabetes were primarily
focused on restoring immune tolerance, which in healthy individuals is
achieved when immune system cells “turn off” so as not to overreact and
attack one’s own cells. In individuals with Type 1 diabetes, the
process of immune tolerance fails to work properly, thereby permitting
the self-destruction of the body’s beta cells.
But lead author Maria Koulmanda, MSc, PhD, director of Non-Human
Primate Research in BIDMC’s Transplantation Research Center, wondered
if there might also be a role for inflammation in the disease process.
“We knew that in cases of type 2 [non-insulin dependent] diabetes, a
form of inflammation in muscle and fat prevents insulin from triggering
the transfer of glucose from the blood into important insulin-sensitive
tissues,” explains Koulmanda, who is also Assistant Professor of
Surgery at HMS. “We thought that in addition to autoimmune destruction
of insulin-producing cells, there might also be inflammation-induced
insulin resistance [in type 1 diabetes.]”
To test this hypothesis, the authors administered a “cocktail” of three
separate agents (rapamycin plus agonist IL-2- and antagonist-type,
mutant IL-15-related Ig fusion proteins) in a NOD (non-obese diabetes)
mouse model of type 1 diabetes. The therapy regimen, which included two
novel immunoglobulin-fusion proteins, was aimed at both increasing
tolerance and decreasing inflammation.
As predicted, following two to four weeks of treatment, the mice that
had received the triple therapy maintained normal levels of blood
sugar. In contrast, the control group of diabetic mice did not survive,
despite receiving insulin.
The authors then conducted a molecular analysis which confirmed that
the treatment had eliminated insulin resistance and relieved
inflammation in the animals’ fat and muscle tissues.
“Although the treatment halted the progressive loss of insulin
producing cells, the restoration of normal blood glucose levels
actually was the result of inflammation being ablated in fat and muscle
cells,” explains Strom. “By blocking the inflammation, we were able to
restore the animals’ abilities to respond to insulin.”
“Our findings are very promising,” adds Koulmanda. “Type 1 diabetes is
a serious disease requiring that children and young adults take insulin
two to three times a day.”
And, she adds, despite this arduous therapy, insulin treatment does not
prevent the occurrence of serious late-arising complications, including
kidney failure, blindness and widespread cardiovascular disease.
“In clinical practice, it is not currently possible to identify when
and if an individual will develop type 1 diabetes,” says Koulmanda.
“Therefore, it is urgent to identify treatments that can restore normal
blood glucose levels in patients with new-onset diabetes before
insulin-producing cells are totally destroyed. We hope that our
findings offer new hope in the long search for a cure of type 1
diabetes.”
This study was funded by grants from the Juvenile Diabetes Research Foundation and the National Institutes of Health.
In addition to Koulmanda and Strom, coauthors include BIDMC
investigators Prabhakar Putheti, PhD, Nicolas Degauque, MD, Zhigang
Fan, MD, Hang Shi, PhD, Xin Xiao Zheng, MD, and Jeffrey Flier, MD;
Ejona Budo MSc, Andi Qipo, MD, and Hugh Auchincloss, Jr., MD, of
Massachusetts General Hospital; and Susan Bonner-Weir, PhD of Joslin
Diabetes Center.
Beth Israel Deaconess Medical Center is a patient care, teaching and
research affiliate of Harvard Medical School and ranks third in
National Institutes of Health funding among independent hospitals
nationwide. BIDMC is clinically affiliated with the Joslin Diabetes
Center and is a research partner of the Dana-Farber/Harvard Cancer
Center. BIDMC is the official hospital of the Boston Red Sox. For more
information, visit www.bidmc.harvard.edu.
