Genetic Disruption of Adenosine Kinase in Mouse Pancreatic β-Cells Protects Against High-Fat Diet-Induced Glucose Intolerance

Islet beta-cells adapt to insulin resistance through increased insulin secretion and expansion. Type 2 diabetes typically occurs when prolonged insulin resistance exceeds the adaptive capacity of beta-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate beta-cell replication. Here, we evaluated whether ADK disruption in mouse beta-cells affects beta-cell mass and/or protects against high-fat diet (HFD)-induced glucose dysregulation. Mice targeted at the Adk locus were bred to Rip-Cre and Ins1-Cre/ERT1Lphi mice to enable constitutive (beta ADKO) and conditional (i beta ADKO) disruption of ADK expression in beta-cells, respectively. Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion (GSIS) were longitudinally monitored in normal chow (NC)-fed and HFD-fed mice. In addition, beta-cell mass and replication were measured by immunofluorescence-based islet morphometry. NC-fed adult beta ADKO and i beta ADKO mice displayed glucose tolerance, insulin tolerance and beta-cell mass comparable to control animals. By contrast, HFD-fed beta ADKO and i beta ADKO animals had improved glucose tolerance and increased in vivo GSIS. Improved glucose handling was associated with increased beta-cell replication and mass. We conclude that ADK expression negatively regulates the adaptive beta-cell response to HFD challenge. Therefore, modulation of ADK activity is a potential strategy for enhancing the adaptive beta-cell response.