Direct and indirect effects of insulin on hepatic glucose production in diabetic depancreatized dogs during euglycemia.

Insulin suppresses glucose production (GP) via both extrahepatic (indirect) and hepatic (direct) effects. We have shown that the direct effect, undetectable in moderately hyperglycemic diabetic dogs, is restored by insulin-induced euglycemia. The first aim of the present study was to determine whether euglycemia per se, and not the excess insulin needed to obtain it, restores the direct effect of insulin on GP. Basal insulin was given portally in depancreatized dogs to attain only moderate hyperglycemia, then an additional insulin was given portally or peripherally to match the peripheral insulin levels and thus to obtain a greater hepatic insulinization with portal delivery. Plasma glucose was allowed to fall to euglycemia before a euglycemic clamp was performed. During euglycemia, there was a tendency (P=0.075) for greater suppression of GP by portal than peripheral insulin. Also, there was a significantly different effect of time (P=0.01) on GP in the two groups, with greater suppression over time in the portal group. The second aim was to test the hypothesis that because of inadequate hepatic insulinization and consequent lack of direct inhibition of GP, peripheral insulin replacement requires peripheral hyperinsulinemia to achieve euglycemia. Portal or peripheral insulin was given to achieve euglycemia and basal GP, and insulin levels were measured. More peripheral insulinemia was required with peripheral than portal insulin replacement to maintain similar euglycemia and GP. Our conclusions are as follows: (1) euglycemia per se is sufficient to acutely restore the direct effect of insulin on GP and (2) at euglycemia, peripheral replacement of insulin, as in insulin-treated diabetes, results in peripheral hyperinsulinemia but unchanged basal GP.

Insulin inhibits glucose production by a direct effect in diabetic depancreatized dogs during euglycemia.

In our previous studies in nondiabetic dogs and humans, insulin suppressed glucose production (GP) by both an indirect extrahepatic and a direct hepatic effect. However, insulin had no direct effect on GP in diabetic depancreatized dogs under conditions of moderate hyperglycemia. The present study was designed to investigate whether insulin can inhibit GP by a direct effect in this model under conditions of euglycemia. Depancreatized dogs were made euglycemic (approximately 6 mmol/l), rather than moderately hyperglycemic (approximately 10 mmol/l) as in our previous studies, by basal portal insulin infusion. After approximately 100 min of euglycemia, a hyperinsulinemic euglycemic clamp was performed by giving an additional infusion of insulin either portally (POR) or peripherally at about one-half the rate (1/2 PER) to match the peripheral venous insulin concentrations. The greater hepatic insulin load in POR resulted in greater suppression of GP (from 16.5 +/- 1.8 to 12.2 +/- 1.6 micromol. kg(-1). min(-1)) than 1/2 PER (from 17.8 +/- 1.9 to 15.6 +/- 2.0 micromol. kg(-1). min(-1), P < 0.001 vs. POR), consistent with insulin having a direct hepatic effect in suppressing GP. We conclude that the direct effect of insulin to inhibit GP is present in diabetic depancreatized dogs under conditions of acutely induced euglycemia. These results suggest that, in diabetes, the prevailing glycemic level is a determinant of the balance between insulin's direct and indirect effects on GP.