Role Of Adenosine Kinase In Pancreatic Beta Cell Proliferation And Regeneration In Mice

Introduction;Absolute or relative deficiency of insulin producing pancreatic β-cells contributes to the development of both type 1 and type 2 diabetes.However,the β cells of human islets have a very short proliferation window,which normally ends after childhood.Therefore,diabetes patients normally cannot compensate for islet β-cell loss and there is great interest in searching for pharmacological reagents to increase β-cell proliferation under different diabetic pathological conditions.Recent pharmacological studies have suggested that increased pancreatic β-cell proliferation could be due to specific inhibition of adenosine kinase(ADK).However,genetic evidence for the function of pancreatic β-cell ADK under physiological conditions or in a pathological context is still lacking.Objectives;The objective of the present study was to explore the effect conditional genetic deletion of adenosine kinase of pancreatic β-cell in glucose homeostasis,β-cell proliferation,β-cell regeneration and restoration of β-cell mass in vivo.Methods;Mice carrying a LoxP-flanked Adk gene were crossed with Ins2-Cre mice to acquire pancreatic β-cell ADK deficiency(Ins2-Cre+/-Adkfl/fl)mice.They were administered and treated in vivo with different treatment and sacrificed,then plasma and tissue samples were obtained.Western blotting,immunofluorescence,RT-PCR,ELISA,and Glucose metabolism tests were used to obtain our results.Results;Our results revealed that Ins2-Cre+/-Adkfl/fl mice showed improved glucose metabolism(P value≤ 0.001),and β-cell proliferation as well as a β-cell mass in younger mice(P value≤0.01),but showed normal activity in adult mice in the physiological context.Moreover,Ins2-Cre+/-Adkfl/fl mice were more resistant to streptozotocin(STZ)induced hyperglycemia and pancreatic β-cell damage in adult mice,which was proved by significant increase of β-cell regeneration,(P value≤0.01).Conclusion;In conclusion,our study exhibit that adenosine kinase has a negative effect on pancreatic beta cell function.Our study provided genetic evidence that specific inhibition of pancreatic β-cell ADK has the potential for anti-diabetic therapy.Proved by improved glucose homeostasis reflected in increased of insulin secretion and efficient glucose tolerant.The improvement of glucose homeostasis was a consequence of increased β-cell mass and expansion of β-cell.