Effect of JTT-501 on net hepatic glucose balance and peripheral glucose uptake in alloxan-induced diabetic dogs.
JTT-501, a new insulin sensitizer, improves peripheral glucose uptake in insulin-resistant animals such as KK-Ay mice and Zucker fatty rats. However, the effect of JTT-501 on hepatic glucose metabolism has not been addressed. To investigate this effect, experiments were performed on 6 alloxan-diabetic dogs. Three experiments were conducted for each dog: the treatment experiment, which followed a 10-day oral treatment with JTT-501 30 mg x kg(-1) x d(-1), and 2 control experiments 2 weeks before and 2 weeks after the treatment experiment. A hyperinsulinemic-hyperglycemic clamp was performed with the tracer dilution method (intraportal insulin infusion rate, 18 pmol x kg(-1) x min(-1)). Arterial hyperglycemia (approximately 10 mmol/L) was maintained by adjusting the peripheral glucose infusion rate. After a 45-minute basal period (period I), portal glucose infusion (22.2 micromol x kg(-1)min(-1)) was administered for 120 minutes (period II). This was followed by a 90-minutes recovery period (period III). JTT-501 increased insulin-stimulated glucose utilization (P < .05) and enhanced insulin-mediated suppression of glucose production (P < .05) in periods I and III. Net hepatic glucose balance (NHGB) determined by the arterial-venous (A-V) difference method was increased by JTT-501 in period II (P < .01). We conclude that JTT-501 enhances both hepatic and peripheral insulin sensitivity and therefore may have important therapeutic effects in type 2 diabetes.
Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan.
M
M
Niwa
S
S
Rashid
K
K
Shum
J M
JM
Mathoo
O
O
Chan
V
V
Tchipashvili
R
R
Kawamori
M
M
Vranic
A
A
Giacca
D000496:Alloxan; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004285:Dogs; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007555:Isoxazoles / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D007555:Isoxazoles; D000496:Alloxan; D005934:Glucagon; D005947:Glucose; C112329:JTT 501