The mechanism of postprandial insulin sensitization first described by Lautt and co-workers
as the HISS (hepatic insulin sensitizing substance) machinery is not completely understood.
We therefore studied the initial step in this mechanism leading to enhanced sensitivity
of the peripheral tissues to the hypoglycemic action of insulin. Whole body insulin
sensitivity was determined by the rapid insulin sensitivity test (RIST) or hyperinsulinemic
euglycemic glucose clamping (HEGC) both in fasted and fed animals. The effect of cholecystokinin
(CCK) was studied by means of a non-selective inhibitor of CCK receptor diazepam (5mg/kg
i.v.) and CCK-1 receptor specific antagonist proglumide (1–30mg/kg i.v.). Proglumide
was also used by intraportal (1mg/kg i.p.) administration to investigate its possible
hepatic site of action. Intravenous administration of diazepam or proglumide during
steady state of the HEGC caused transient hyperglycemia. Insulin sensitivity was suppressed
by proglumide in a dose dependent manner in fed animals and the RIST index (mg/kg
glucose needs to maintain euglycemia) was 202.2±9.4, 159.4±19.4, 154.6±15.6, 101.6±6.7
and 94.2±11.8 in the solvent-, 1, 3, 10 and 30mg/kg proglumide treated fed animals,
respectively. In fasted animals the RIST index was 113.1±6.8 and 97.3±10.4 in the
solvent-, and 10mg/kg proglumide treated animals, respectively. The dose of proglumide
that failed to suppress insulin sensitivity at systemic use caused transient hyperglycemia
when infused into the portal vein in fed animals. This work is the first to describe
the involvement of CCK in the initial step of the activation of postprandial insulin
sensitization.
