Insulinopenia and persistent hyperglycaemia was induced in experimental mice using low dose streptozotocin (STZ, 60 mg/kg, freshly dissolved in 0.05 M sterile sodium citrate, pH 4.5) on five successive days in 8-week-old mice as described5 (link),17 (link),19 . To study the consequences of insulin resistance db/db mice were used. For further details see supplementary information.
Subgroup of mice received various interventions. We intraperitoneally injected either tauroursodeoxycholic acid (TUDCA) (150 mg/kg bodyweight, dissolved in saline) or saline once daily starting 18 weeks after the last streptozotocin (STZ) injection until 1 d before analyses (week 26) in some mice5 (link). In other mice we intraperitoneally injected aPC (1 mg/kg bodyweight, every alternate day) or an equal volume of saline. Aditionally, in a subgroup of mice aPC was pre-incubated before injection with the HAPC1573 antibody at a 1:1 ratio for 10 min under gentle agitation to block its anticoagulant activity20 (link),21 (link). Human aPC was used throughout the study, which was generated following an established protocol22 (link).