Type 2 diabetes mellitus (T2DM) has become an epidemic. This metabolic disease is marked by insulin resistance in conjunction with progressive loss of beta cell number and function. This relative insulinopenia results from a combination of beta cell dysfunction and loss of beta cell mass. We previously identified the adipokine adipsin, which is reduced in obesity, as a critical regulator of pancreatic beta cell function in murine models of T2DM. Adipsin helps to generate the C3a peptide to effect a signal through its receptor C3aR1 on the beta cell. Our new data show that chronic adipsin treatment of diabetic db/db mice staves off the diabetic complication of beta cell failure. Adipsin downregulates the phosphatase DUSP26 which results in improved beta cell survival. In this proposal, we seek to follow up on these studies and assess the mechanisms behind the protective effects of chronic adipsin treatment. We will pursue the following specific aims: 1. Define the physiological role of the C3aR1 receptor on beta cells using a beta cell specific knockout of C3aR1 in mice. We will determine the requirement of the C3aR1 receptor in maintaining beta cell homeostasis in vivo. 2. Define the role of the phosphatase DUSP26 in regulating beta cell identity and survival. The overall goal of these studies will shed light on how the adipsin/C3a/C3aR1/DUSP26 pathway can be used to maintain long term beta cell health to treat patients with T2DM.

Public Health Relevance

Type 2 diabetes mellitus (T2DM) has become an epidemic disease that is marked by insulin resistance in conjunction with progressive loss in number and function of the insulin producing beta cell. Despite the advancements made with new diabetes medications, there are currently no therapies that have been proven to be effective in restoring beta cell function and numbers for T2DM patients once beta cell failure has ensued. In this proposal, we aim to develop new therapies that can be used to prevent or treat pancreatic beta cell failure in T2DM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK121140-02
Application #
10080727
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2020-01-06
Project End
2023-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065