FK-614, a selective peroxisome proliferator-activated receptor gamma agonist, improves peripheral glucose utilization while decreasing hepatic insulin extraction in alloxan-induced diabetic dogs.
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.
Uchino
Hiroshi
H
Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Kim
Tony
T
Lam
Tony K T
TK
Yoshii
Hidenori
H
Klement
Peter
P
Williams
Wendy
W
Kawamori
Ryuzo
R
Giacca
Adria
A
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
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