title: FK-614, a selective peroxisome proliferator-activated receptor gamma agonist, improves peripheral glucose utilization while decreasing hepatic insulin extraction in alloxan-induced diabetic dogs.
abstract: This is the first report of the effects of a nonthiazolidinedione activator of peroxisome proliferator-activated receptor (PPAR) gamma, that is, FK-614 (a benzimidazole derivative), on glucose metabolism in vivo. To investigate the effect of FK-614 on peripheral and hepatic insulin action, we performed hyperinsulinemic-hyperglycemic clamp studies combined with the triple-catheter technique and a double-tracer approach in alloxan-diabetic dogs with (n=5) or without (n=6) treatment with FK-614 (0.32 mg/kg per day orally for 10 days). Throughout the experiment, insulin was infused intraportally at 18 pmol/kg per minute and hyperglycemia (approximately 11 mmol/L) was maintained by a peripheral glucose infusion. After a 45-minute basal period (period I), a portal infusion of glucose labeled with [U-14C]-glucose, was administered for 120 minutes (period II) to measure hepatic glucose uptake. This was followed by 90-minute recovery (period III). FK-614 marginally improved peripheral insulin sensitivity, did not affect hepatic glucose uptake, and surprisingly increased tracer-determined hepatic glucose production (19.0+/-5.0 vs 10.6+/-1.7 mumol/kg per minute, P<.001). Hepatic insulin extraction was decreased by FK-614 (47.8%+/-1.6% vs 55.9%+/-3.4%, P<.01), which led to greater peripheral insulin levels and glucose utilization. FK-614 treatment also decreased the daily insulin requirements (regular insulin, 0.18+/-0.01 vs 0.32+/-0.01 U/kg per day; and NPH insulin, 0.53+/-0.02 vs 0.89+/-0.04 U/kg per day; P<.001) to maintain fasting plasma glucose at approximately 10 mmol/L for 7 days before the experiments. We conclude that FK-614 treatment, at the dose used, improves peripheral glucose utilization because of an improvement in peripheral insulin sensitivity and a decrease in insulin clearance, but impairs hepatic insulin action in alloxan-induced diabetic dogs. The reason for the effects of FK-614 on hepatic glucose and insulin metabolism is unclear but they are both consistent with reports of hepatic steatosis by PPARgamma activation when unopposed by concomitant activation of PPARalpha.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchino
authors.forename: Tony
authors.initials: T
authors.lastname: Kim
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yoshii
authors.forename: Peter
authors.initials: P
authors.lastname: Klement
authors.forename: Wendy
authors.initials: W
authors.lastname: Williams
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Kawamori
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D004285:Dogs; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D007336:Insulin, Isophane / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D014316:Tritium
chemical_list: C496142:3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3 H-benzimidazole-5-carboxamide; D001562:Benzimidazoles; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D014316:Tritium; D007336:Insulin, Isophane; D005934:Glucagon; D005947:Glucose