The role of cholecystokinin in the enhancement of postprandial insulin sensitivity

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.