Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene therapy technique could aid islet transplants for diabetes, says Pittsburgh study

05.02.2004


Researchers also find current immunosuppression drug therapy may be harmful for transplanted Islets



Treating pancreatic islet cells with a growth factor can dramatically reduce the number of these cells needed for transplants to reverse Type 1 diabetes, according to a study by University of Pittsburgh School of Medicine researchers. In the animal model study, researchers also found that the triple-drug immunosuppression therapy currently used after human islet cell transplants is harmful to transplanted rat pancreatic islets and can actually induce diabetes in rats.

"This study suggests that the current immunosuppression regimen might be further optimized or changed and has potential implications for further improving islet transplant outcomes in humans with Type 1 diabetes," said senior author Andrew Stewart, M.D., chief of the division of endocrinology and metabolism and professor of medicine at the University of Pittsburgh School of Medicine.


The research is published in the February 2004 issue of the journal Endocrinology and on line at http://endo.endojournals.org/.

"On the positive side, by using a rat model that closely mimics events occurring in human islet transplant recipients, we found that introducing a growth factor DNA to pancreatic islet beta cells (the cells that produce insulin) before transplantation induces cell division and greatly enhances the cells’ function and survival," said Dr. Stewart. "That is good news for the 1.6 million people with Type 1 diabetes because the procedure may help surmount difficulties currently posed by the limited availability of human pancreatic islet cells.

"The disappointing news is that we also discovered, much to our surprise, that the three immunosuppressive drugs commonly prescribed for patients after islet cell transplantation induced marked insulin resistance and beta cell toxicity in the models used in our studies, actually inducing diabetes and reducing the function of their new islet cells. This was true even though the doses and the blood levels of the drugs were low and comparable to those used in humans."

In the study, the researchers used a common virus called an adenovirus to deliver hepatocyte growth factor (HGF), which induces beta cell division and prolongs beta cell survival, into pancreatic islets that had been extracted from rat pancreases. Having conducted similar previous research on genetically immunodeficient mice, researchers this time sought to construct a situation that most closely mimics a human islet cell transplant according to the Edmonton protocol. They used an allogenic islet transplant system, using islets from Lewis rats and transplanting them into Sprague Dawley rats (this is similar to transplanting islets from one human donor into a different recipient). They also delivered the islets into the portal vein (as is performed in humans) instead of through a kidney capsule graft (used in their prior studies in mice). Finally, researchers used the standard combination of immunosuppressive drugs – tacrolimus, sirolimus and daclizumab.

After one day, and lasting three weeks, the blood glucose control was far superior in the HGF-treated rats than the controls. Also, the number of islets surviving in the liver in rats that had been transplanted with HGF-treated islets was double that seen with controls, whose transplanted islets had been treated with a control adenovirus. These studies confirmed prior studies from the Pittsburgh group demonstrating the efficacy of HGF in enhancing islet transplant outcomes.

The experiment was then repeated, going beyond three weeks to see if the improvements would be long lasting. As had been observed previously, but this time for 18 weeks, rats whose islets had been pre-treated with HGF maintained blood glucose levels 200 mg/dl lower than the control animals. Since rats live for approximately two years, this could equate to a decade or more in a human.

Surprisingly, however, in control studies, completely normal rats treated with the triple-drug regimen developed markedly increased blood glucose levels, reaching 250 mg/dl in only ten days. In addition, the blood insulin levels increased by three-fold, indicating that these normal rats had become insulin resistant as a result of the triple drug treatment. (Insulin resistance is the cause of Type 2 diabetes, commonly encountered in adults.) In the second, longer study, the control rats all remained diabetic throughout the study and died by week 18 with blood glucose levels in the 400 mg/dl range.

"We have demonstrated that using gene therapy strategies to deliver a growth factor, in this case HGF, to islet cells can improve the efficacy of portal pancreatic islet transplants over the long term using a model of juvenile, or Type 1, diabetes," said Dr. Stewart. "However, the fact that even the non-diabetic, non-transplanted control rats developed severe diabetes with the standard immunosuppressive drug therapy used following human islet cell transplants makes me wonder whether the same might not be occurring in humans, thereby increasing the number of islets needed for successful transplant outcomes and ultimately causing failure of islet grafts. These issues now need to be studied in humans."

"In brief, in my view, the Edmonton protocol for the transplantation of islets is a modern miracle. Our work suggests further optimism: there still may be room for further improvement," Dr. Stewart concluded.

The Edmonton Protocol to treat Type 1 diabetes was developed by researchers at the University of Alberta in Edmonton, Canada. Doctors use ultrasound to guide placement of a small catheter through the upper abdomen and into the liver. Pancreatic islet cells are then injected through the catheter into the liver. In time, islets are established in the liver and begin releasing insulin.


This work was supported by a research grant from the Juvenile Diabetes Research Foundation. The research team was composed of Juan Carlos Lopez-Talavera, M.D., currently at Roche Pharmaceuticals in Nutley, N.J., Adolfo Garcia-Ocana, Ph.D., assistant professor at the University of Pittsburgh School of Medicine, and Irene Cozar Castellano, Ph.D., postdoctoral fellow at the university, and was supported by Karen Takane, Ph.D., research associate at the university and Mr. Ian Sipula, BS, laboratory technician.

CONTACT:
Frank Raczkiewicz
Alan Aldinger
PHONE: 412-647-3555
FAX: 412-624-3184
E-MAIL:
RaczkiewiczFA@upmc.edu
AldiAL@upmc.edu

Frank Raczkiewicz | EurekAlert!
Further information:
http://www.upmc.edu/
http://endo.endojournals.org/

More articles from Health and Medicine:

nachricht Team discovers how bacteria exploit a chink in the body's armor
20.01.2017 | University of Illinois at Urbana-Champaign

nachricht Rabies viruses reveal wiring in transparent brains
19.01.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>