INSULIN ACUTELY SUPPRESSES GLUCOSE-PRODUCTION BY BOTH PERIPHERAL AND HEPATIC-EFFECTS IN NORMAL DOGS

To determine whether the predominant effect of insulin in suppressing tracer-determined glucose production (R-a) is hepatic or peripheral, w e infused insulin peripherally (PER) and portally (FOR) at both low (0 .75 pmol.kg(-1).min(-1)) and high physiological rates (2.7 pmol.kg(-1) .min(-1)) during euglycemic clamps in normal dogs. We also infused ins ulin peripherally at one-half these rates (1/2 PER) to match the perip heral insulin levels in FOR and thus obtain a selective FOR vs. 1/2 PE R difference in hepatic insulin levels. At the high-rate insulin infus ion, peripheral insulin levels were greatest with PER (PER = 212 +/- 1 0 pM, n = 5; FOR = 119 +/- 5 pM, n = 6; 1/2 PER = 122 +/- 5 pM, n = 6) . Calculated hepatic insulin levels were greatest with FOR (FOR = 227 +/- 13 pM, PER = 206 +/- 19 pM, 1/2 PER = 123 +/- 8 pM). High-dose PER yielded a greater suppression of R-a than FOR (79 +/- 18 vs. 56 +/- 6 %, P < .001). R-a was only suppressed by 45 +/- 6% with 1/2 PER (P < 0 .01 vs. FOR on 6 paired experiments). Free fatty acid (FFA) was suppre ssed by 57 +/- 8% with PER and only by 33 +/- 5 and 37 +/- 2% with FOR and 1/2 PER, respectively. The low-dose PER and FOR yielded an equal R-a suppression (PER = 46 +/- 9%, FOR = 43 +/- 4%). Only 1/2 PER was a ssociated with a lower suppression of R-a (36 +/- 8, P < 0.05 vs. FOR) . FFA showed similar suppression in all three groups (similar to 25%). Using both insulin infusion rates, the percent R-a suppression per un it difference in peripheral insulin was approximately twofold greater than that per unit difference in hepatic insulin. These results sugges t that, during euglycemic clamps without somatostatin in normal dogs, R-a suppression is mediated by both peripheral and hepatic effects of insulin and that peripheral insulin, at least at high physiological in fusion rates, is more potent than hepatic insulin in suppressing R-a.