FK-614, a selective peroxisome proliferator-activated receptor γ 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) γ, 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 (∼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 μmol/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 PPARγ activation when unopposed by concomitant activation of PPARα.