Islet amyloid polypeptide (IAPP) deposits in the pancreas in about 90% of patients with type-2 diabetes. The extent of amyloid deposition correlates with the reduction in insulin producing beta-cells, indicating that these amyloidogenic aggregates or their oligomeric precursors may be toxic to beta-cells. The goal of this project is to develop immunotherapy to clear these deposits and/or prevent their formation. This approach may then reverse or slow the progression of diabetes and/or prevent its onset. Towards this end, various derivatives of IAPP, designed to be non-amyloidogenic while maintaining its immunogenicity, will be characterized in vitro to confirm their predicted secondary structure and non-toxic properties. Subsequently, transgenic mice for the human IAPP that develop pancreatic amyloid deposits will be vaccinated with these immunogens. The diabetic state of the animals will be assessed periodically during the experiment. At the end of the study, the efficacy of this treatment will be assessed by measuring beta-cell numbers and amyloid burden in the pancreas as well as insulin levels and related biochemical markers. This type of immunotherapy has been successful in models for other amyloidoses such as Alzheimer's-, prion- and Parkinson's disease as demonstrated by us and others. These prior findings support the feasibility of this project and there is currently no therapy available that directly targets pancreatic IAPP aggregates. ? Currently, about 16 million individuals in the United States are considered to have type-2 diabetes although only about 7.2 million have been diagnosed, and worldwide about 150 million are estimated to suffer from the disease. Deposition of islet amyloid polypeptide in the pancreas is found in over 90% of subjects with this form of diabetes and this peptide is likely to have a prominent role in disease onset and progression. Our proposed immunotherapeutic approach is designed to clear and/or prevent the formation of these amyloid deposits. We and others have had success with similar approaches in other amyloid diseases such as Alzheimer's-, prion-, and Parkinson's disease. These studies could lead to novel treatments for type-2 diabetes. ? ? ?
