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Department of Physiology, Medicine, and Surgery, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and Department of Medicine, University of Chicago, Chicago, Illinois 60637
To determine whether the predominant effect of
insulin in suppressing tracer-determined glucose production
(Ra) is hepatic or peripheral,
we infused insulin peripherally (PER) and portally (POR) at both low
(0.75 pmol · kg
1 · min1)
and high physiological rates (2.7 pmol · kg1 · min1)
during euglycemic clamps in normal dogs. We also infused insulin peripherally at one-half these rates (1/2 PER) to match the peripheral insulin levels in POR and thus obtain a selective POR vs. 1/2 PER
difference in hepatic insulin levels. At the high-rate insulin infusion, peripheral insulin levels were greatest with PER (PER = 212 ± 10 pM, n = 5; POR = 119 ± 5 pM, n = 6; 1/2 PER = 122 ± 5 pM, n = 6). Calculated hepatic
insulin levels were greatest with POR (POR = 227 ± 13 pM, PER = 206 ± 19 pM, 1/2 PER = 123 ± 8 pM). High-dose PER yielded a greater
suppression of Ra than POR (79 ± 18 vs. 56 ± 6%, P < .001). Ra was only suppressed by 45 ± 6% with 1/2 PER (P < 0.01 vs. POR on 6 paired experiments). Free fatty acid (FFA) was
suppressed by 57 ± 8% with PER and only by 33 ± 5 and 37 ± 2% with POR and 1/2 PER, respectively. The low-dose PER and POR
yielded an equal Ra suppression
(PER = 46 ± 9%, POR = 43 ± 4%). Only 1/2 PER was associated
with a lower suppression of Ra (36 ± 8, P < 0.05 vs. POR). FFA
showed similar suppression in all three groups (~25%). Using both
insulin infusion rates, the percent
Ra suppression per unit difference
in peripheral insulin was approximately twofold greater than that per
unit difference in hepatic insulin. These results suggest that, during
euglycemic clamps without somatostatin in normal dogs,
Ra suppression is mediated by both
peripheral and hepatic effects of insulin and that peripheral insulin,
at least at high physiological infusion rates, is more potent than
hepatic insulin in suppressing Ra.
portal-peripheral insulin gradient; glucose turnover; gluconeogenic precursors; free fatty acids; glucagon
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