TY - JOUR T1 - Oral administration of NPC43 counters hyperglycemia and activates insulin receptor in streptozotocin-induced type 1 diabetic mice JF - BMJ Open Diabetes Research & Care JO - BMJ Open Diab Res Care DO - 10.1136/bmjdrc-2020-001695 VL - 8 IS - 1 SP - e001695 AU - Zi-Jian Lan AU - Zhenmin Lei AU - Lucinda Nation AU - Xian Li AU - Alexandros Yiannikouris AU - Thirupathi Reddy Yerramreddy AU - Hayley Kincaid AU - Katie Eastridge AU - Rijin Xiao AU - Ryan Goettl AU - Ronan Power Y1 - 2020/09/01 UR - http://drc.bmj.com/content/8/1/e001695.abstract N2 - Introduction Adenosine, 5’-Se-methyl-5’-seleno-,2’,3’-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 Insrβ, 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’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 Insrβ, 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. ER -