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Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada M5G 2C4
We have shown
previously that the greater suppression of endogenous glucose
production (GP) with equimolar peripheral vs. portal insulin cannot be
detected or is minimally reversed when the insulin-induced suppression
of either free fatty acids (FFA) or glucagon alone is prevented. The
present experiments were designed to minimize the insulin suppression
of both glucagon and FFA in an attempt to further examine the mechanism
of insulin's peripheral effect on GP. In nine healthy men, we
investigated the effect of limiting the insulin suppression of both FFA
and glucagon by infusing heparin (250 U/h), Intralipid 10% (25 ml/h),
and glucagon (0.65 ng · kg
1 · min1)
during 1) portal
(n = 9),
2) equimolar peripheral
(n = 9), and 3) half-dose peripheral insulin
delivery (n = 4) by use of our previously published tolbutamide infusion method, with calculation and
matching of insulin secretion rate. GP decreased by 57.2 ± 2.6%
with portal, 39.0 ± 4.1% with equimolar peripheral, and 31.5 ± 2.7% with half-dose peripheral insulin delivery
(P < 0.001 for portal vs. peripheral
and P < 0.001 for portal vs.
half-dose peripheral). In contrast, in six control subjects in whom
glucagon and FFA were not replaced, GP decreased by 62.6 ± 2.4%
with portal (n = 6), 75.7 ± 3.0%
with peripheral (n = 6), and 56.3 ± 3.0% with half-dose peripheral
(n = 4) insulin delivery
(P < 0.01 for portal vs. peripheral
and P = not significant for portal vs.
half-dose peripheral). In summary, the greater suppression of GP with
equimolar peripheral vs. portal insulin is eliminated and markedly
reversed if the acute insulin-induced suppression of both plasma FFA
and glucagon is minimized. This suggests that the insulin-induced suppression of glucagon and FFA has additive or cooperative effects in
mediating the acute extrahepatic effect of insulin on GP.
portal vein; tolbutamide; glucose clamp technique
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