Chemists identify key gene in development of type 1 diabetes

03/07/05

SAN DIEGO, March 17 Chemists say they have identified a gene that appears to play a key role in the development of type 1 diabetes, also known as insulin-dependent or juvenile diabetes, a disease that affects about one million people in the U.S. and is on the rise worldwide. They described their findings, which they say could lead to new drug interventions and possibly gene therapy, today at the 229th national meeting of the American Chemical Society, the world's largest scientific society.

In the current study, the researchers focused on the formation of the MIF protein (macrophage migration inhibitory factor), a proinflammatory protein that they showed in previous studies is elevated in diabetic animals and may be involved in the cascade of immunological events that leads to the destruction of the pancreas and the subsequent onset of type 1 diabetes. The disease is much less common than type 2 diabetes, formerly known as adult onset or non-insulin-dependent diabetes, which is often associated with obesity.

"We've shown that the MIF gene is crucial for the development of type 1 diabetes," says study leader Yousef Al-Abed, Ph.D., a chemist at the Institute for Medical Research of the North Shore-Long Island Jewish (LIJ) Health System in Manhasset, N.Y. "It is not the only factor involved in this complex disease, but it is certainly a promising target for its prevention and treatment."

In preliminary studies by the research group, specially bred mice that lacked the gene for the MIF protein failed to develop diabetes compared to mice that possessed the gene, according to the investigators. Although it's likely that multiple genes are involved in the formation of diabetes, the finding provides proof of concept that efforts to block the formation of this particular protein is a promising approach for fighting diabetes, they say.

"The MIF gene may be regulating other genes involved in type 1 diabetes," says Al-Abed. "We don't know yet, but we're looking into this." Besides drug intervention, the new finding could lead to gene therapy to prevent the disease, possibly by disrupting the network of genes involved in its development, he says.

A potential drug treatment based on blocking the MIF protein is already being explored. In a study presented last year at an ACS national meeting, the researchers reported they were able to prevent diabetes in a group of mice by using a synthetic compound called ISO-1 to block the MIF protein. If human studies prove the effectiveness of ISO-1, the compound or its derivatives could ultimately save lives, reduce health care costs and help prediabetic people, particularly children, avoid a lifetime of insulin injections, Al-Abed says. Prediabetic individuals are those who have blood markers either antibodies or genetic markers that are predictive of the disease but are still able to produce insulin.

Al-Abed and his associates hope that the experimental compound can one day be developed into a long-acting oral drug that could be taken by prediabetic people to achieve lasting protection, perhaps a lifetime. But such a drug would take years to develop and test, the researchers caution. Likewise, effective gene therapy against the disease may take many years to develop, they add.

Besides prevention, ISO-1 also is being tested in animals to determine whether it will help in the actual treatment of ongoing type 1 diabetes and type 2 diabetes, the more common type. Results are not yet available from these tests, the researchers say.

Although nobody knows the exact cause of type 1 diabetes, and there is no cure, the disease can be controlled and its complications minimized by following a healthy diet, getting exercise and taking prescribed medications as directed, according to health experts.

The Institute for Medical Research at North Shore-LIJ provided funding for this study.

The American Chemical Society is a nonprofit organization, chartered by the U.S. Congress, with a multidisciplinary membership of more than 159,000 chemists and chemical engineers. It publishes numerous scientific journals and databases, convenes major research conferences and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.

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The paper on this research, MEDI 581, will be presented at 10:00 a.m. on Thursday, March 17 at the Convention Center, Room 6B, during the symposium, "General Oral Session." Yousef Al-Abed, Ph.D., is an associate investigator and director of the Laboratory of Medicinal Chemistry at the Institute for Medical Research at North Shore-LIJ in Manhasset, N.Y. He is also an associate professor of medicine at New York University School of Medicine in Manhattan, NY.

Mark T. Sampson

MEDI 581 MIF knockout mice are resistant to the development of type 1 diabetes

Yousef Al-Abed1, Ivana Cvetkovic2, Djordje Miljkovic2, Christine Metz1, Ferdinando Nicoletti3, and Stanislava Stosic-Grujicic2. (1) Laboratory of Medicinal Chemistry, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030, Fax: 1-516-365-5090, yalabed@nshs.edu, (2) Institute for Biological Research "Sinisa Stankovic", (3) University of Catania

We have recently shown that MIF protein is significantly elevated in islet cells during the development of experimental diabetes induced in mice by multiple low doses of streptozotocin. Attenuation of MIF activity with neutralizing antibodies against MIF, or the pharmacological MIF inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), markedly reduces histopathological changes in the islets of pancreas and suppresses the development of hyperglycaemia. The observed beneficial effects could be attributed to the reduced proliferation and adhesion of autoreactive lymphocytes, down-regulation of iNOS expression, as well as NO and TNF secretion by islets of pancreas and by peritoneal macrophages. Our successful approach to prevent or treat the development of type 1 diabetes using anti-MIF treatments, prompted us to examine the role of MIF deletion in the disease process. In contrast to wild-type mice, we found that mice lacking MIF gene are resistant to the development of type 1 diabetes using the streptozotocin approach.

Briefly explain in lay language what you have done, why it is significant and what are its implications (particularly to the general public)

Type 1 diabetes mellitus (DM) afflicts approximately four million people in North America and studies show that it is on the rise worldwide. Type 1 diabetes mellitus (type 1 DM, or diabetes) is a multifactorial syndrome due to a body's inability to make insulin. Normally, insulin is manufactured in the pancreas in cells called "beta cells." In people with type 1 DM, the beta cells are attacked by the immune system (specifically by macrophages and T lymphocytes) and killed, so that insulin can no longer be made. Despite extensive research efforts to understand the key role of proinflammatory mediators in the development of type 1 diabetes, no effective anti-inflammatory therapeutic has been approved for the clinical management of type 1 DM. We have recently discovered that MIF, a proinflammatory protein, is a critical mediator of the development of type 1 diabetes. Our studies can be summarized as follows: 1. Prevention of type 1 diabetes development: We recently have discovered that macrophage migration inhibitory factor (MIF) is a small protein that plays a central role in the regulation of the immune system, plays also a critical role in the onset of type 1 diabetes in murine. We therefore, have investigated the activity of MIF as well as the influence of MIF activity neutralization during the development of type 1 diabetes in an experimental model of type 1 diabetes. For this purpose, we first raised the question whether neutralization of MIF with its antibody is beneficiary in preventing the disease onset. We therefore, have investigated the activity of MIF as well as the influence of MIF activity neutralization during the development of type 1 diabetes using STZ, a chemical that is been used globally to induce type 1 diabetes in murine. We found that administration of the anti-MIF antibody prior to giving STZ blocked the onset of diabetes in mice when compared to those mice that received the vehicle. Various immunological parameters relevant for type 1 DM were similar to the control (non-diabetic) animals.

To our knowledge, this is the first attempt to interfere in autoimmune diabetes by in vivo neutralization of MIF (in vivo means "in a living body". 2. Development of a medicinal treatment for type 1 diabetes: Because antibody therapy is not practical, a more desirable approach is to develop a non-toxic pharmacological molecule that would specifically block the MIF role in inducing type 1 diabetes. We have recently discovered that ISO-1, a small molecule inhibitor of MIF pro-inflammatory activity in vitro and in vivo that was designed by our laboratory, at 20 mg/kg completely inhibited the onset of diabetes in two animal models of STZ-induced diabetes. The inhibition results because ISO-1 binds to a critical site on the surface of the MIF protein, which prevents further communication with its inflammatory network. This protection was comparable to antibody treatment using anti-MIF antibody. 3. Deletion of MIF gene: Proof of concepts Our successful approach to prevent the development of type 1 diabetes using anti-MIF treatments, prompted us to examine the role of MIF deletion in the disease process. MIF knockout mice were successfully produced in 1999.

To confirm the critical role of MIF in the development of type 1 diabetes, we investigated the development of type 1 diabetes in MIF lacking the MIF gene. In contrast to wild-type mice, we found that mice lacking MIF gene are resistant to the development of type 1 diabetes using the STZ approach. It is important to note that such a critical role of MIF in the development of type 1 diabetes is unique among other cytokines that were investigated by gene deletion for their role in this disease. 4. Treatment of type 1 diabetes with ISO-1 Previously, we have shown that anti-MIF antibody and ISO-1 can prevent type 1 diabetes. Prevention strategy is being sought in the context of diabetes, due to the presence of several markers such as Familial and other antibodies in our circulation that can identify the children with high risk factor to be diabetic.

Herein, we would like to address our new approach to treat the disease when it is diagnosed in the early stage. Most diabetic children are identified when the disease still in the early stage suggesting that there is room for protection (saving) of non-destructed beta cells. Such a strategy will save the islet as well as suppress or block the inflammatory process in the early stage and consequently prevent the pancreas from being attacked by foreign cells. We tested the effect of treatment with ISO-1 at a later stage of the disease development. To that extent, ISO-1 was administered to mice after mice were challenged (treated) with multiple STZ injections. Our data revealed that this late short-term treatment with ISO-1 significantly reduces blood glucose levels in comparison to control diabetic mice. These data provide evidence for critical role of MIF in the induction and progression of immunoinflammatory diabetes. Taken together, these data provide evidence for critical role of MIF in the induction and progression of immunoinflammatory DM.

How new is this work and how does it differ from that of others who may be doing similar research?

This is a continuation of our effort to treat and prevent type 1 diabetes. The role of MIF gene deletion in animal model of type 1 diabetes is new. This study confirmed for the first time that MIF is a target for preventing or treating type 1 diabetes. Once we proved that MIF knockout mice are resistant to the development of type 1 diabetes, we then examined whether anti-MIF treatments could attenuate the disease progress in its early stage. Indeed, our small molecule, ISO-1, reverted the disease development. All these findings are new.

Yousef Al-Abed
Laboratory of Medicinal Chemistry
North Shore-LIJ Research Institute
350 Community Drive
Manhasset, NY 11030
Phone Number: 1-516-562-9461
Fax Number: 1-516-365-5090
Publishable Email: yalabed@nshs.edu

The paper on this research, MEDI 581, will be presented at 10:00 AM, Thursday, March 17, 2005, at the Room 6B (Convention Center), Room Room 6B, during the symposium, "General Oral Session".

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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