Influence of oral sulfonylurea agents on hepatic glucose uptake

Although the metabolic derangement in the subjects with well-established NIDDM is characterized by both insulin resistance and diminished insulin secretion, the impaired sensitivity to insulin in the target tissues is assumed to represent the primary defect in most NIDDM individuals. Therefore, the therapeutic modality that can augment insulin-mediated glucose metabolism in the target tissues seems rational in the treatment of NIDDM. Glimepiride (HOE490), a newly developed sulfonylurea, has been reported to have a more potent hypoglycemic action than glibenclamide while its ability to stimulate insulin secretion is much weaker. Thus, part of the potent hypoglycemic action of HOE490 has been speculated as being due to an extrapancreatic effect. First we examined the effect of strict glycemic control on insulin resistance seen in NIDDM using euglycemic hyperinsulinemic clamp combined with oral glucose loading (Clamp-OGL) to 9 subjects with NIDDM. After 3 to 4 weeks of intensified insulin therapy, insulin-mediated glucose uptake by the liver significantly increased while peripheral glucose disposal did not change. Secondly we applied Clamp-OGL to 5 subjects with IDDM to study the acute metabolic effect of HOE490 on glucose handlings by the target tissues. Intravenous administration of HOE490 at a rate of 6.0 μg/min did not affect hepatic glucose uptake in these subjects. Thus we studied subacute metabolic effect of HOE490 on glucose handlings by the target tissues in 7 normal dogs using euglycemic clamp combined with hepatic venous catheterization technique. After 7-day consecutive oral administration of HOE490 (0.1 mg/kg/day), net hepatic glucose balance during portal glucose infusion showed a marked elevation and this explained most of the increment in the systemic glucose utilization. These results indicate that rather short-term oral administration of HOE490 has a stimulatory effect on the insulin-mediated glucose uptake predominantly by the liver when glucose is loaded via a physiological route. Whether HOE490 has similar effect on the hepatic glucose disposal in the subjects with NIDDM, should be examined.