The impact of Type II diabetes disease is increasing with the expanding percentage of the elderly within our population. Therefore there is an urgent need for medical procedures to cure this disease. Type II diabetes develops due to a combination of decreased insulin secretion and a decrease in the body's response towards insulin. A key factor in the development of Type II diabetes is the loss of insulin producing beta-cells. The membrane interactions, misfolding and aggregation of human Islet Amyloid Polypeptide (hIAPP) is believed to play crucial roles in this process. Previous studies have shown that hIAPP forms small aggregates that kill beta-cells by disrupting the cellular membrane. However, it is not known exactly what causes this process, how hIAPP disrupts the cell's membrane, and, most importantly, how it can be stopped. In this study we propose to use solid-state NMR spectroscopy and other biophysical techniques to address these questions. We will use fluorescence experiments to understand the kinetics of hIAPP aggregation and to determine the conditions for high-resolution studies using solid-state NMR spectroscopy. Solid-state NMR studies will provide insights into the catalytic role of membranes on the formation of misfolded and toxic forms of hIAPP, and the process of membrane-disruption by hIAPP. This information will be essential to understand what makes some individuals susceptible to Type II diabetes and why Type II diabetes strikes late in life. In addition, solving the high-resolution structure of hIAPP in physiologically-relevant membranes using solid-state NMR techniques will answer why some forms of IAPP (such as the human form) are toxic and others (such as the rat form) with very similar sequences are not. These high-resolution structures will guide the development of drugs to stop the loss of insulin production because of beta cell death. Although the proposed study is focused on hIAPP, the outcome will be of importance to other aging-related diseases such as Alzheimer's disease and Parkinson's disease.

Public Health Relevance

Type II diabetes develops due to a combination of decreased insulin secretion and a decrease in the body's response towards insulin. A key factor in the development of Type II diabetes is the loss of insulin producing beta-cells. The proposed studies will give an understanding of the mechanism of how beta-cells are killed by IAPP and may serve to guide the design of drugs to block the toxic effect of IAPP on insulin producing beta-cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK078885-02
Application #
7748945
Study Section
Special Emphasis Panel (ZRG1-EMNR-L (90))
Program Officer
Sechi, Salvatore
Project Start
2009-01-01
Project End
2011-03-31
Budget Start
2010-01-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$184,970
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biophysics
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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