The current type 2 diabetes (T2DM) pandemic affects more than 347 million individuals worldwide and is a major healthcare concern for the foreseeable future. Given the enormous healthcare burden associated with T2DM, there is an urgent need for improved therapies. One therapeutic strategy is to maintain euglycemia by increasing an individual's ?-cell mass and insulin secretion capacity. Recently, small molecule inhibitors of the enzyme adenosine kinase (ADK) were demonstrated to promote the proliferation of ?-cell but not other cell types.(1) This discovery has led to the hypothesis that ADK inhibitors represent a new class of diabetes therapeutics that function by increasing ?-cell growth. Unfortunately, the ADK inhibitors that are currently available have central nervous system side-effects that prevent their long-term use in vivo. In addition, animals that are globall deficient in ADK are nonviable. Therefore, to test the in vivo function of ADK within ?-cells it wa necessary to generate genetically modified mice that allow ADK expression to be disrupted in a cell-type specific and a temporally controlled manner. This proposal describes the use of these mice to characterize the expression pattern of ADK and to test if disrupting ADK expression within ?-cells increases islet ?-cell replication and mass. This work has the potential to validate a new therapeutic strategy for the treatment of diabetes.

Public Health Relevance

Type 2 diabetes is an affliction that affects approximately 25 million Americans and is estimated to have an associated annual healthcare cost of 174 billion dollars. While diet and exercise are critical interventions, they are unsuccessful at preventing or reversing diabetes in most individuals even when used in combination with medications. We propose to test a new therapeutic approach to diabetes that works by increasing the number of insulin producing cells and thereby prevents high blood sugar levels.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
Project #
Application #
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Navarro, Guadalupe; Abdolazimi, Yassan; Zhao, Zhengshan et al. (2017) Genetic Disruption of Adenosine Kinase in Mouse Pancreatic ?-Cells Protects Against High-Fat Diet-Induced Glucose Intolerance. Diabetes 66:1928-1938
Zhao, Zhengshan; Abdolazimi, Yassan; Armstrong, Neali A et al. (2016) A High-content In Vitro Pancreatic Islet ?-cell Replication Discovery Platform. J Vis Exp :
Zhao, Zhenshan; Low, Yen S; Armstrong, Neali A et al. (2014) Repurposing cAMP-modulating medications to promote ?-cell replication. Mol Endocrinol 28:1682-97
Nichols, Robert J; New, Connie; Annes, Justin P (2014) Adult tissue sources for new ? cells. Transl Res 163:418-31