Insulin receptor binds insulin for glucose uptake, but also acts as a chemotactic receptor for insulin. Therefore, cells with a high density of insulin receptor expression on their surface can physically move toward a concentrated source of insulin. The most concentrated source of insulin in the body are beta cells in pancreatic islets. This project is concerned with the ability of insulin receptor expressing cells to move into the pancreas. Our laboratory has shown that purified high density insulin receptor expressing splenic T cells obtained from diabetic NOD mice can transfer insulitis and diabetes into young nondiabetic irradiated NOD recipient mice. However, purified insulin receptor negative T cells did not transfer either insulitis or diabetes. Recent work has shown preliminary evidence that insulin receptor expression engineered onto T cells in a C57Bl/6 transgenic strain of mice leads to cell movement into the pancreas. Non transgenic C57Bl/6 mice do not exhibit insulitis. However, diabetes does not develop in the transgenic mice. This proposal seeks to determine whether insulin receptor expression is a mechanism that supports T cell movement into the pancreas in mice and in human type 1 diabetes. Blocking of chemotaxis to insulin would provide a new therapeutic target for type 1 diabetes.

Public Health Relevance

Chronic inflammation is the prolongation of inflammation where damage to the tissue occurs due to continual migration of lymphocytes to the affected area. Blocking this migration process will prevent continued tissue destruction and alleviate the disease condition. Instead of general immunosuppressants we are focused on blocking homing of T lymphocytes specifically targeted to insulin producing cells in the pancreas in an effort to develop new targets for evidence based drug therapy in type 1 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15DK103196-01
Application #
8773541
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (81))
Program Officer
Spain, Lisa M
Project Start
2014-09-08
Project End
2017-06-30
Budget Start
2014-09-08
Budget End
2017-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$453,553
Indirect Cost
$154,178
Name
University of Toledo
Department
Biochemistry
Type
Schools of Pharmacy
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614