title: The effect of pioglitazone on hepatic glucose uptake measured with indirect and direct methods in alloxan-induced diabetic dogs.
abstract: Pioglitazone, a thiazolidinedione derivative, ameliorates hyperglycemia by augmenting peripheral glucose disposal and suppressing hepatic glucose production in diabetic animals. However, the effect of this agent on hepatic glucose uptake has not been explored. To determine this, experiments were conducted in alloxan-induced diabetic dogs with (pioglitazone group, n = 7) or without (control group, n = 5) a 10-day oral treatment with pioglitazone (1 mg x kg(-1) x day(-1)). A euglycemic-hyperinsulinemic (insulin infusion rate 25.2 pmol x kg(-1) x min(-1)) clamp was maintained by adjusting the peripheral glucose infusion rate (GIR). After a 60-min basal period (period I), portal glucose infusion (Pinf, 33.3 micromol x kg(-1) x 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; 1,712 +/- 52 pmol/l, C group). There was no significant difference in whole-body glucose utilization determined by [3-3H]glucose between the pioglitazone and C groups in period I (68.4 +/- 2.8 vs. 70.1 +/- 2.8 micromol x kg(-1) x min(-1), respectively) and period III (81.2 +/- 5.0 vs. 74.5 +/- 3.3 micromol x kg(-1) x min(-1), respectively). Net hepatic glucose uptake (NHGU) determined by arteriovenous difference method was approximately zero in the basal period (-0.7 +/- 1.1, pioglitazone group; 0.1 +/- 1.2 micromol x kg(-1) x min(-1), C group). In period II, hepatic glucose uptake, determined by the changes in GIR, was significantly higher in the pioglitazone group (6.5 +/- 0.6 micromol x kg(-1) x min(-1)) than in the C group (-0.4 +/- 0.6 micromol x kg(-1) x min(-1), P < 0.001). This observation was also confirmed by NHGU during portal glucose infusion (6.9 +/- 1.4 vs. 2.1 +/- 1.8 micromol x kg(-1) x min(-1), pioglitazone vs. C, respectively; P < 0.025). We conclude that pioglitazone treatment enhances hepatic glucose uptake during portal glucose loading in alloxan-induced diabetic dogs. However, in hyperinsulinemic conditions, pioglitazone does not enhance the already high peripheral glucose uptake.
authors.affiliation: Department of Physiology, University of Toronto, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Matsuhisa
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Shi
authors.forename: C
authors.initials: C
authors.lastname: Wan
authors.forename: M
authors.initials: M
authors.lastname: Lekas
authors.forename: C D
authors.initials: CD
authors.lastname: Rodgers
authors.forename: A
authors.initials: A
authors.lastname: Giacca
authors.forename: R
authors.initials: R
authors.lastname: Kawamori
authors.forename: M
authors.initials: M
authors.lastname: Vranic
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004285:Dogs; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D000077205:Pioglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D005934:Glucagon; D005947:Glucose; D000077205:Pioglitazone