Diabetes currently affects 9.3% of the U.S. population totaling $245 billion annually in U.S. healthcare costs. Current therapies for diabetes are limited in their ability to control blood glucose and/or enhance insulin sensitivity. Given the magnitude of diabetes costs and complications, new therapies with reduced side effects are urgently needed. The common defect in both type 1 and type 2 diabetes is the loss of functional pancreatic islet ?-cell mass. A therapeutic intervention that replenishes the insulin-producing pancreatic beta cells represents a cure for diabetes We propose to develop two distinct molecular scaffolds with demonstrated in vivo proof of concept for stimulating pancreatic beta-cell proliferation. A series of phenylbenzamides, discovered in an unrelated hepatic steatosis screen, were found to stimulate selective beta cell proliferation in rodents, isolated rat and human islets, and will be evaluated and optimized for efficacy and translational potential. The second series - chromenones, discovered in a Nkx6.1 promoter screen, have been shown to robustly stimulate beta-cell proliferation in rodent and human islets. We will perform medicinal chemistry optimization on both scaffolds to produce in vivo chemical probes with translational potential for human therapeutic use.

Public Health Relevance

Diabetes and diabetes-related co-morbidities are a major burden to our healthcare system. Despite numerous classes of diabetes drugs, only ~36% of diabetes patients achieve satisfactory glycemic control. Therefore, novel treatment modalities for diabetes are desperately needed. We have discovered two classes of compounds that selectively stimulate pancreatic ?-cell proliferation in rodents and in human islet tissue in culture. This lead optimization proposal utilizes a robust high-content ?-cell proliferation assay to guide compound selection for follow-up in vivo analysis of ?-cell proliferation. We seek to deliver small molecule chemical probes that stimulate ?-cell proliferation in cultured islet tissue and in vivo with therapeutic potential for human use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK120623-02
Application #
9902446
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Li, Yan
Project Start
2019-04-01
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109