M. Matsuhisa et al., THE EFFECT OF PIOGLITAZONE ON HEPATIC GLUCOSE-UPTAKE MEASURED WITH INDIRECT AND DIRECT-METHODS IN ALLOXAN-INDUCED DIABETIC DOGS, Diabetes, 46(2), 1997, pp. 224-231
Pioglitazolae, a thiazolidinedione derivative, ameliorates hyperglycem
ia by augmenting peripheral glucose disposal and suppressing hepatic g
lucose production in diabetic animals. However, the effect of this age
nt on hepatic glucose uptake has not been explored, To determine this,
experiments were conducted in alloxan-induced diabetic dogs with (pio
glitazone group, n = 7) or without (control group, n = 5) a 10-day ora
l treatment with pioglitazone (1 mg . kg(-1) . day(-1)). A euglycemic-
hyperinsulinemic (insulin infusion rate 25.2 pmoI . kg(-1) . min(-1))
clamp was maintained by adjusting the peripheral glucose infusion rate
(GIR). After a 60-min basal period (period I), portal glucose infusio
n (Pinf, 33.3 mu mol . kg(-1) . min(-1)) was administered for 120 min
(period II). This was followed by a 60-min recovery period (period III
). Arterial insulin levels were kept stable in the supraphysiological
range throughout the experiment (1,623 +/- 52, pioglitazone group; 1,7
12 +/- 52 pmol/l, C group). There was no significant difference in who
le-body glucose utilization determined by [3-H-3]glucose between the p
ioglitazone and C groups in period I (68.4 +/- 2.8 vs. 70.1 +/- 2.8 mu
moI . kg(-1) . min(-1), respectively) and period III (81.2 +/- 5.0 vs
. 74.5 +/- 3.3 mu mol . kg(-1) . min(-1), respectively). Net hepatic g
lucose uptake (NHGU) determined by arteriovenous difference method was
approximately zero in the basal period (-0.7 +/- 1.1, pioglitazone gr
oup; 0.1 +/- 1.2 mu mol . kg(-1) . min(-1), C group). In period II, he
patic glucose uptake, determined by the changes in GIR, was significan
tly higher in the pioglitazone group (6.5 +/- 0.6 mu mol . kg(-1) . mi
n(-1)) than in the C group (-0.4 +/- 0.6 mu mol . k(-1) . min(-1), P <
0.001). This observation was also confirmed by NHGU during portal glu
cose infusion (6.9 +/- 1.4 vs. 2.1 +/- 1.8 mu mol . kg(-1) . min(-1),
pioglitazone vs. C, respectively;P < 0.025). We conclude that pioglita
zone treatment enhances hepatic glucose uptake during portal glucose l
oading in alloxan-induced diabetic clogs, However, in hyperinsulinemic
conditions, pioglitazone does not enhance the already high peripheral
glucose uptake.