BOSTON - A key obstacle to early detection of type 1 diabetes - as wellas to rapid assessment of the effectiveness of therapeutic intervention- has been the lack of direct, non-invasive technologies to visualizeinflammation in the pancreas, an early manifestation of disease.Instead, clinicians have had to await overt symptoms before diagnosingan individual, by which time destruction of the insulin-producing betacells of the pancreas has already progressed significantly.
Recent proof-of-principle experiments by Joslin Diabetes Center andMassachusetts General Hospital (MGH) researchers, however, offer hopethat physicians may one day be able to identify individuals withpreclinical type 1 diabetes, and to assess the effectiveness oftherapies much earlier than is now possible. Findings of the study willbe published in the September issue of the Journal of ClinicalInvestigation.
Type 1 diabetes is an autoimmune disease in which the body'simmune system mistakenly attacks its own insulin-producing beta cellsand eventually kills them. Early in this process, white blood cellscalled T lymphocytes infiltrate the islets of the pancreas (aninflammatory condition known as insulitis), causing the blood vesselsto become leaky. Over time, this infiltration of lymphocytes destroysthe beta cells, leading to high blood glucose and full-blown diabetes.Today, the only accurate method for detecting the progression orregression of insulitis is a biopsy of the pancreas, which is almostnever performed because it is an invasive and potentially riskyprocedure.
"The most exciting aspect of this study is that itdemonstrates that we can, at least in mice, use a non-invasive imagingmethod to predict at a very early time whether a drug will stop theprogression of diabetes or not. In fact, the drug we used in theseproof-of-principle experiments is analogous to one currently beingtried in humans with diabetes, and so far showing great promise," saidDiane Mathis, Ph.D., who led the study together with ChristopheBenoist, M.D., Ph.D., also from Joslin, and Ralph Weissleder, M.D.,Ph.D., of MGH.
Drs. Mathis and Benoist head Joslin's Section on Immunologyand Immunogenetics, hold William T. Young Chairs in Diabetes Researchat Joslin, and are Professors of Medicine at Harvard Medical School.Other investigators in the study included Stuart Turvey, M.D., Ph.D.,formerly of Joslin, who is now at the University of British Columbiaand British Columbia Children's Hospital, both in Vancouver, Canada;Maria Denis, Ph.D., a former Joslin research fellow who now works atthe BSRC Alexander Fleming Institute of Immunology in Greece, and EricSwart and Umar Mahmood, M.D., Ph.D., from MGH.
In this study, the Joslin and MGH researchers used a newimaging technique to reveal the otherwise undetectable inflammation ofpancreatic islets in recently diagnosed diabetic mice. As T lymphocytesinvade the pancreas, blood vessels swell, become more permeable, andleak fluid -- as well as small molecules carried in the fluid -- intosurrounding tissues. In previous experiments, the researchersdemonstrated that this leakage can be detected with the help ofmagnetic nanoparticles (MNP) and magnetic resonance imaging (MRI).After being injected intravenously, these MNPs, which are minuteparticles of iron oxide, travel through the blood vessels of the bodyincluding the pancreas. If pancreatic vessels have become leaky frominflammation, the magnetic particles spill into nearby tissues, wherethey are "eaten" by scavenger cells called macrophages. Thus, the MNPsbecome concentrated at the inflamed site and can be spotted byhigh-resolution MRI.
In their recent study, the researchers applied the MRI-MNPtechnique to determine whether they could predict which mice woulddevelop autoimmune diabetes and monitor the effectiveness of immunetherapy aimed at reversing diabetes. The goal of this study was togather data on mouse models that could guide the safe application ofthe technique in human patients with, or at risk of, type 1 diabetes.
Results of this study suggest that the MRI-MNP imagingtechnology may be helpful in identifying people at immediate risk ofdeveloping autoimmune diabetes, but most of all for early prediction ofresponse to therapy, which might be very useful for reducing the timeand cost of clinical trials. "Because the results in mice looked sogood, and because our MGH colleagues have already successfully usedessentially the same drug on many patients with prostate cancer," saidDr. Benoist, "we have been able to move relatively quickly intoclinical trials." Dr. Turvey added: "We hope to know soon whether wecan use this drug and imaging technique to monitor pancreasinflammation in humans."
Now Recruiting for Clinical Trial
Joslin investigators are currently recruiting subjects for theImaging in Diabetes clinical trial. Subjects must be individuals overthe age of 17 who have been diagnosed with type 1 diabetes within thelast six months or who are at increased risk for developing type 1diabetes, based on family history and antibody testing. At present, thetrial is enrolling only at-risk individuals who have already been riskstratified. Qualified individuals interested in more information aboutthis trial should contact Jason Gaglia at Joslin Diabetes Center at617-732-2481 or [email protected].
About Joslin Diabetes Center
Joslin Diabetes Center, dedicated to conquering diabetes in all of itsforms, is the global leader in diabetes research, care and education.Founded in 1898, Joslin is an independent nonprofit institutionaffiliated with Harvard Medical School. Joslin research is a team ofmore than 300 people at the forefront of discovery aimed at preventingand curing diabetes. Joslin Clinic, affiliated with Beth IsraelDeaconess Medical Center in Boston, the nationwide network of JoslinAffiliated Programs, and the hundreds of Joslin educational programsoffered each year for clinicians, researchers and patients, enableJoslin to develop, implement and share innovations that immeasurablyimprove the lives of people with diabetes. As a nonprofit, Joslinbenefits from the generosity of donors in advancing its mission. Formore information on Joslin, call 1-800-JOSLIN-1 or visit www.joslin.org.
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