Dynamics of hepatic and peripheral insulin effects suggest common rate-limiting step in vivo

Abstract

This study compares the dynamics and sensitivity of hepatic and peripheral insulin action in conscious dogs. Glucose turnover was measured simultaneously by HOT GINF tracer methodology and by hepatic AV differences. SRIF was infused during euglycemic clamps to suppress endogenous insulin and glucagon secretion. Basal plasma glucagon levels were recreated by intraportal replacement (2 ng.min-1 x kg-1), and insulin was infused intraportally at 0, 3, 6, 10, or 20 pmol.min-1 x kg-1 for 3 h. Steady-state HGO and NHGO were suppressed by insulin with EC50s of 164 and 95 pM, respectively. As expected, these were lower than the EC50 for Rd stimulation (516 pM), demonstrating greater hepatic than peripheral insulin sensitivity. In contrast to sensitivity, dynamics for suppression of HGO and NHGO and for stimulation of Rd by insulin were indistinguishable: half-times averaged 43 +/- 5, 42 +/- 9, and 45 +/- 5 min, respectively (P > 0.77). For all three variables, the half-time of insulin effect was independent of insulin dose (P > 0.26). The striking similarity of the time courses for suppression of glucose production and stimulation of glucose uptake suggests that both effects are secondary manifestations of a single, rate-limiting phenomenon. We hypothesize this single gateway to insulin action is transendothelial insulin transport, which we previously have shown to be rate limiting for insulin's effect on glucose uptake in vivo.