1. Genetic Disruption of Adenosine Kinase in Mouse Pancreatic β-Cells Protects Against High-Fat Diet-Induced Glucose Intolerance.
- Author
-
Navarro G, Abdolazimi Y, Zhao Z, Xu H, Lee S, Armstrong NA, and Annes JP
- Subjects
- Animals, Blotting, Western, Fluorescent Antibody Technique, Glucose Intolerance metabolism, In Vitro Techniques, Insulin Resistance, Insulin-Secreting Cells pathology, Islets of Langerhans metabolism, Islets of Langerhans pathology, Mice, Mice, Knockout, Organ Size, Weight Gain, Adenosine Kinase genetics, Blood Glucose metabolism, Diet, High-Fat, Glucose Intolerance genetics, Insulin-Secreting Cells metabolism
- Abstract
Islet β-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 β-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate β-cell replication. Here, we evaluated whether ADK disruption in mouse β-cells affects β-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/ERT
1Lphi mice to enable constitutive (βADKO) and conditional (iβADKO) disruption of ADK expression in β-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, β-cell mass and replication were measured by immunofluorescence-based islet morphometry. NC-fed adult βADKO and iβADKO mice displayed glucose tolerance, insulin tolerance and β-cell mass comparable to control animals. By contrast, HFD-fed βADKO and iβADKO animals had improved glucose tolerance and increased in vivo GSIS. Improved glucose handling was associated with increased β-cell replication and mass. We conclude that ADK expression negatively regulates the adaptive β-cell response to HFD challenge. Therefore, modulation of ADK activity is a potential strategy for enhancing the adaptive β-cell response., (© 2017 by the American Diabetes Association.)- Published
- 2017
- Full Text
- View/download PDF