THE EFFECT OF PIOGLITAZONE ON HEPATIC GLUCOSE-UPTAKE MEASURED WITH INDIRECT AND DIRECT-METHODS IN ALLOXAN-INDUCED DIABETIC DOGS

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.