AMP deaminase-2- and adenosine deaminase-mediated disposal of β-cell intracellular adenosine protects against multiple low-dose streptozotocin-induced type 1 diabetes

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Objective To evaluate the importance of AMPD2 and ADA, two adenosine disposal enzymes, for β-cell survival and the development of T1D . Methods The nucleotide metabolism in EndoC-βH1 cells was compared with that of α-TC1–6 cells using HPLC and enzyme activity analysis. AMPD2 and ADA activities were modulated using a synthetic target site blocker (TSB) in vitro and in vivo . The multiple low-dose streptozotocin (MLDSTZ) mouse model was used to study T1D. Results EndoC-βH1 cells contained higher AMP and P-AMPK levels than α-TC1–6 cells, and these levels were further increased during stress. ADA and AMPD enzyme activities were lower in β-cells. Extracellular adenosine lowered human islet insulin contents without affecting glucagon contents. Downregulation of AMPD2 resulted in lower inosine levels and increased cell death. An AMPD2 miR141–3p miRNA TSB increased AMPD2 levels, reduced adenosine levels, and decreased β-cell death. Treatment of MLDSTZ mice with the AMPD2 TSB resulted in lower blood glucose and higher serum insulin levels, an increased β-cell area and reduced activated caspase-3. The AMPD2 TSB treatment resulted in decreased expression of IFN-γ, IL-17 and IL-10 in CD8 + T-cells on day 7, and an increase in IL-10 + macrophages on day 21. An ADA miR140–3p TSB protected partially against T1D, an effect which was further increased when combined with the AMPD2 TSB. Conclusions β-cells differ from α-cells in terms of the metabolism and disposal of intracellular adenosine, which makes β-cells more vulnerable to ATP-depleting stress, and therefore also more prone to being attacked by the immune system in T1D.