It has long been known that type 1 diabetes is an autoimmune disease. The body attacks the islet cells in the pancreas that produce insulin. In recent years, the immune system has also been implicated in type 2 diabetes — in particular imbalances in cytokines, an immune system component that causes inflammation.
These imbalances become especially marked as people become obese. Dr. Jerry Nadler and his colleagues are investigating the role of a key gene — 12/15-LO (12/15-lipoxygenase ) — that has been implicated in the immune-system induced inflammatory effects linked to both forms of diabetes and their complications.
It is not obesity in and of itself that causes type 2 diabetes. Research done with knockout mice — mice that are genetically engineered to have inoperative genes — has demonstrated that the 12/15-LO gene is the culprit. Knockout mice that lack the 12/15-LO gene do not develop diabetes, even when fed an extremely high-fat diet. This gene is present in the insulin-producing cells of the pancreas, and when activated causes the cells to malfunction. It is also expressed by macrophages, a type of white blood cell. “Under normal conditions, this gene is probably involved in cell development,” Nadler says. “It’s only in pathologic conditions that the gene is activated in adults.”
Macrophages appear in high concentrations in fatty tissue. With funding from the National Institutes of Health, Nadler has traced the mechanism by which the presence of large numbers of fat cells stimulate the macrophages to activate the 12/15-LO gene, and has documented the cascade of inflammatory reactions that results. He has found that the 12/15-LO gene produces two proteins that convert fatty acids into cytokines.
Nadler’s work suggests a number of approaches for therapies. With funding from the Ella Fitzgerald Charitable Foundation, he is developing a diagnostic test to measure the activation of this gene in people. Working with Dr. Ross Isaacs, associate professor of medicine, he is developing a test to identify one of the proteins produced by 12/15-LO, a substance called 12[S]-HETE (12[S]-Hydroxyeicosatetraenoic acid). “This could serve as an early marker of kidney disease,” Nadler says.
In Nadler’s view, blocking 12/15-LO activation could provide a new therapeutic way to protect pancreatic beta cells from inflammation. “This is a particularly promising line of research,” Nadler says. “The expression of this gene is also implicated in heart and blood vessel disease and in nerve cell death associated with Alzheimer’s disease.”
Nadler is also collaborating with Dr. Marcia McDuffie, professor of microbiology, to identify the role of 12/15-LO in type 1 diabetes. Eliminating the gene in a mouse model provides over 90 percent protection from developing the disease, an exciting early result.
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