@article {Lane001695, author = {Zi-Jian Lan and Zhenmin Lei and Lucinda Nation and Xian Li and Alexandros Yiannikouris and Thirupathi Reddy Yerramreddy and Hayley Kincaid and Katie Eastridge and Rijin Xiao and Ryan Goettl and Ronan Power}, title = {Oral administration of NPC43 counters hyperglycemia and activates insulin receptor in streptozotocin-induced type 1 diabetic mice}, volume = {8}, number = {1}, elocation-id = {e001695}, year = {2020}, doi = {10.1136/bmjdrc-2020-001695}, publisher = {BMJ Specialist Journals}, abstract = {Introduction Adenosine, 5{\textquoteright}-Se-methyl-5{\textquoteright}-seleno-,2{\textquoteright},3{\textquoteright}-diacetate (NPC43) is a recently identified small, non-peptidyl molecule which restores normal insulin signaling in a mouse model of type 2 diabetes (Lan et al). The present study investigated the ability of NPC43 as an oral and injectable insulin-replacing agent to activate insulin receptor (INSR) and counter hyperglycemia in streptozotocin (STZ)-induced type 1 diabetic (T1D) mice.Research design and methods In this study, STZ was intraperitoneally injected into wild-type mice to induce hyperglycemia and hypoinsulinemia, the main features of T1D. These STZ-induced T1D mice were given NPC43 orally or intraperitoneally and blood glucose levels were measured using a glucometer. Protein levels of phosphorylated and total InsrĪ², protein kinase B (Akt) and AS160 (critical for glucose uptake) in the skeletal muscle and liver of STZ-induced T1D mice following oral NPC43 treatment were determined by western blot analysis. In addition, hepatic expression of activated Insr in STZ-induced T1D mice after intraperitoneal NPC43 treatment was measured by ELISA. Student{\textquoteright}s t-test was used for statistical analysis.Results Oral administration of NPC43 at a dose of 5.4 or 10.8 mg/kg body weight (mpk) effectively lowered blood glucose levels in STZ-induced T1D mice at >=1 hour post-treatment and the glucose-lowering activity of oral NPC43 persisted for 5 hours. Blood glucose levels were also reduced in STZ-induced T1D mice following intraperitoneal NPC43 (5.4 mpk) treatment. Protein levels of phosphorylated InsrĪ², Akt and AS160 were significantly increased in the skeletal muscle and liver of STZ-induced T1D mice after oral NPC43 (5.4 mpk) treatment. In addition, activation of hepatic Insr was observed in STZ-induced T1D mice following intraperitoneal NPC43 (5.4 mpk) treatment.Conclusions We conclude that NPC43 is a de facto fast-acting oral and injectable insulin mimetic which activates Insr and mitigates hyperglycemia in a mouse model of T1D.}, URL = {https://drc.bmj.com/content/8/1/e001695}, eprint = {https://drc.bmj.com/content/8/1/e001695.full.pdf}, journal = {BMJ Open Diabetes Research and Care} }