News — SAN DIEGO 鈥� (February 24, 2011) 鈥� A research team, led by La Jolla Institute scientist Joel Linden, Ph.D., has shed new light on the problem of insulin resistance, and identified the key participants in a molecular pathway that holds therapeutic promise for reducing the severity of type 2 diabetes. The researchers looked at the role of adenosine, an immune system signaling molecule, in triggering inflammation, which significantly contributes to insulin resistance. Insulin resistance keeps the body from properly handling sugar and is one of the key factors underlying type 2 diabetes. Diabetes now affects nearly 26 million Americans and is the seventh leading cause of death in the U.S., according to the Centers for Disease Control.
鈥淪everal previous studies have shown that if you block adenosine signaling, insulin resistance is diminished,鈥� said Dr. Linden. 鈥淗owever, it wasn鈥檛 known exactly how the process worked or which cells were directly involved.鈥�
Dr. Linden鈥檚 team identified the primary cellular players in the adenosine-fueled inflammation cascade that contributes to insulin resistance. Their study, in animal models, also tested the effectiveness of a recently synthesized adenosine receptor blocker. 鈥淲e found that if you use this molecule to selectively block one of the adenosine receptors, insulin resistance is decreased and diabetes gets better,鈥� said Dr. Linden, one of the world鈥檚 leading authorities on adenosine.
Eugene Barrett, Ph.D., a past president of the American Diabetes Association, praised the study鈥檚 findings as important. "There is a great need for new approaches to lessen the disease burden caused by insulin resistance,鈥� said Dr. Barrett, a professor of medicine and director of the University of Virginia鈥檚 Diabetes Center, which was not involved in the study. 鈥淭he work of Dr. Linden and his collaborators opens a new avenue to explore with possibly important therapeutic implications."
The findings were published in a paper entitled 鈥淟inks Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans鈥� in the February issue of the scientific journal Diabetes. Dr. Linden was senior author on the study, which involved scientists from Pennsylvania State University, the University of Virginia, the La Jolla Institute for Allergy & Immunology and Clinical Data, Inc., a pharmaceutical company examining possible therapeutic applications targeting adenosine receptors. Robert A. Figler, Ph.D., of Clinical Data Inc. was first author on the paper. 鈥淥ur study clarifies the molecular steps triggered by adenosine, which leads to inflammation linked not only to type 2 diabetes but to other inflammatory diseases,鈥� Dr. Figler said. Clinical Data has an ongoing development program in A2B receptor antagonists, he added, and is pursuing the therapeutic potential of these agents in diabetes as well as asthma. Clinical Data plans to soon begin a clinical trial for patients with asthma.
In type 2 diabetes, Dr. Linden explained, the ability of insulin to stimulate glucose uptake by the tissues is reduced, an occurrence known as insulin resistance. 鈥淚nsulin鈥檚 job is to move glucose out of the blood stream and into other body tissues, where it can be used,鈥� he said. 鈥淚f insulin can鈥檛 do its job because the body鈥檚 tissues aren鈥檛 responding to it sufficiently, then you end up with a buildup of sugar in the blood.鈥�
鈥淪o we asked ourselves the question,鈥� Dr. Linden continued, 鈥榳hy don鈥檛 the tissues respond?鈥欌��
Recently, said Dr. Linden, the scientific community has learned that type 2 diabetes is associated with chronic low-grade inflammation. 鈥淲e believe, as do many scientists, that insulin resistance involves macrophages, which are cells of the body that contribute to inflammation,鈥� he explained. 鈥淲e discovered that adenosine stimulates macrophages. The macrophages then release chemicals called cytokines, which are molecules that rev up the immune system. We believe it is the cytokines that cause tissues to become less sensitive to insulin.鈥� By using an adenosine receptor blocker, the team prevented the adenosine from activating the macrophages, said Dr. Linden. 鈥淪o the downstream effect of releasing cytokines does not occur.鈥� The result? The tissues began to better respond to insulin, which reduces blood sugar levels in diabetic animals.
While sensitivity to insulin was significantly improved, Dr. Linden said insulin resistance was not completely reversed. 鈥淲e will be studying this further to better understand the details of insulin resistance,鈥� he said.
About La Jolla InstituteFounded in 1988, the La Jolla Institute for Allergy & Immunology is a biomedical research nonprofit focused on improving human health through increased understanding of the immune system. Its scientists carry out research seeking new knowledge leading to the prevention of disease through vaccines and the treatment and cure of infectious diseases, cancer and autoimmune diseases such as rheumatoid arthritis, type 1 (juvenile) diabetes, Crohn鈥檚 disease and asthma. La Jolla Institute鈥檚 research staff includes more than 100 Ph.D.s and M.D.s. For more information, go to
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