12-Lipoxygenase

1. 12-Lipoxygenase Potential Role in Type I Diabetes

2. Type I Diabetes • Also called autoimmune diabetes • Occurs when the body’s infection-fighting white blood cells start destroying the beta-cells that produce insulin in the pancreas • Requires insulin injections because the body can not produce insulin on its own • Chronic condition affecting nearly 3 million American children and adults

3. Symptoms of Type I Diabetes • Symptoms appear when all the insulin producing cells have been destroyed • Symptoms include • Unexplained weight loss • Vision problems • Frequent urination • Extreme hunger and thirst • Tiredness

4. Severity of Type I Diabetes • Prolonged periods with out insulin injections can lead to serious health complications and even death • Puts individuals at an increased risk for kidney failure, liver damage, heart disease, gum disease, and blindness • Carefully monitor ketone levels

5. Severity of Type I Diabetes • Ketosis Free fatty acids (FFA) released Low blood glucose Fat reserves mobilized Partial oxidation of FFA to ketone bodies Liver uptake of FFA

6. 12-Lipoxygenase • The direct cause of Type I diabetes is not concretely known • Generally understood inflammation plays a vital role in beta cell destruction • 12-Lipoxygenase (12-LO), a protein based enzyme found in beta cells, produces specific lipids that cause inflammation and death of beta cells in laboratory models • Converts Arachadonic acid into pro-inflammatory compounds

7. 12-Lipoxygenase • Metabolism of natural C20 cis fatty acids produces powerful eicosanoids

8. 12-Lipoxygenase • Research on this enzyme has been conducted at Eastern Virginia Medical School’s Strelitz Diabetes Center • Researchers inactivated the gene which produces the 12-lipoxygenase enzyme in female mice • After inactivating the gene in study mice, they discovered these mice were 97% less likely to develop diabetes than mice with normal levels of the enzyme

9. 12-Lipoxygenase • The challenge is to validate that 12-LO and its products have a role in human diabetes • Difficult to gain access to human beta cells • EVMS is among a limited number of research groups who have access to human islets • EVMS team confirmed that 12-LO is indeed found in human islets and its pro-inflammatory lipid products can lead to lower insulin production and beta cell death

10. What Does This Mean? • EVMS is currently working with investigators in California and the National Institutes of Health to identify medications that could target 12-LO as a new treatment • This would halt immune damage to human insulin-producing cells • Prevent Type I Diabetes • In individuals currently suffering from Type I Diabetes, a drug targeting 12-LO could be combined with beta cell regeneration or islet transplantation to produce a cure for the disease.

11. QUESTIONS??