DIRECT AND INDIRECT EFFECTS OF INSULIN IN SUPPRESSING GLUCOSE-PRODUCTION IN DEPANCREATIZED DOGS - ROLE OF GLUCAGON

We have previously shown that during glucose clamps in moderately hype rglycemic depancreatized dogs: 1) peripheral insulin infusion, resulti ng in greater systemic insulinemia and greater suppression of glucagon than equidose portal infusion, inhibited glucose production (GP) to a greater extent; and 2) portal and half-dose peripheral infusions, res ulting in matched peripheral insulinemia and similar suppression of gl ucagon, inhibited GP equally. These findings are consistent with an in direct effect of insulin in suppressing GP in diabetic dogs, which mig ht be partly mediated by the differential suppression of glucagon. To address this question, we performed the experimental protocols of the previous study under conditions of constant glucagon levels (similar t o 550 ng/liter), achieved by a high rate portal glucagon infusion (5 n g/kg . min). As in the previous study (basal glucagon levels, similar to 170 ng/liter), we used depancreatized dogs and assessed GP with HPL C-purified [6-H-3]glucose. After obtaining constant basal hyperglycemi a (similar to 10 mM) with portal infusions of insulin (4.8 +/- 0.5 pmo l/kg . min) and glucagon, an additional infusion of insulin was admini stered for 180 min, either pot-tally (portal; n = 7) or peripherally ( peripheral; n = 8) at the same rate (5.4 pmol/kg . min) or at half tha t rate peripherally (1/2 periph; n = 5). Plasma glucose and glucose sp ecific activities were clamped at basal levels. Systemic insulin level s increased by 215 +/- 16, 310 +/- 26, and 184 +/- 15 pM, and estimate d hepatic insulin levels increased by 398 +/- 20, 310 +/- 26, and 184 +/- 15 pM with portal, peripheral, and 1/2 periph, respectively. GP wa s suppressed to the same extent with portal and peripheral (53 +/- 6% and 50 +/- 6%), but less with 1/2 periph (35 +/- 5%). FFA levels were suppressed to a greater extent with peripheral than portal or 1/2 peri ph, whereas the responses of lactate alanine and glycerol to insulin i nfusion were similar in the three groups. Thus, in the present report, unlike in our previous study, 1) suppression of GP was proportional t o the hepatic insulin levels; and 2) systemic insulin levels did not d ominate suppression of GP. We, therefore, conclude that in hyperglycem ic depancreatized dogs 1) glucagon, at concentrations seen in poorly c ontrolled diabetes, can unmask a direct effect of hepatic insulin leve ls on GP; and 2) the suppression of glucagon may play a role in the pe ripheral effect of exogenously delivered insulin on GP. This is the fi rst in vivo study to show that the main direct effect of insulin on th e liver is to counteract the effect of glucagon.