Interrogating the Role of Adenosine Kinase in Islet Beta-Cells

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): 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.