INFLUENCE OF ORAL SULFONYLUREA AGENTS ON HEPATIC GLUCOSE-UPTAKE

Although the metabolic derangement in the subjects with well-establish ed NIDDM is characterized by both insulin resistance and diminished in sulin secretion, the impaired sensitivity to insulin in the target tis sues is assumed to represent the primary defect in most NIDDM individu als. Therefore, the therapeutic modality that can augment insulin-medi ated glucose metabolism in the target tissues seems rational in the tr eatment of NIDDM. Glimepiride (HOE490), a newly developed sulfonylurea , has been reported to have a more potent hypoglycemic action than gli benclamide while its ability to stimulate insulin secretion is much we aker. Thus, part of the potent hypoglycemic action of HOE490 has been speculated as being due to an extrapancreatic effect. First we examine d the effect of strict glycemic control on insulin resistance seen in NIDDM using euglycemic hyperinsulinemic clamp combined with oral gluco se loading (Clamp-OGL) to 9 subjects with NIDDM. After 3 to 4 weeks of intensified insulin therapy, insulin-mediated glucose uptake by the l iver significantly increased while peripheral glucose disposal did not change. Secondly we applied Clamp-OGL to 5 subjects with IDDM to stud y the acute metabolic effect of HOE490 on glucose handlings by the tar get tissues. Intravenous administration of HOE490 at a rate of 6.0 mu g/min did not affect hepatic glucose uptake in these subjects. Thus we studied subacute metabolic effect of HOE490 on glucose handlings by t he target tissues in 7 normal dogs using euglycemic clamp combined wit h hepatic venous catheterization technique. After 7-day consecutive or al administration of HOE490 (0.1 mg/kg/day), net hepatic glucose balan ce during portal glucose infusion showed a marked elevation and this e xplained most of the increment in the systemic glucose utilization. Th ese results indicate that rather short-term oral administration of HOE 490 has a stimulatory effect on the insulin-mediated glucose uptake pr edominantly by the liver when glucose is loaded via a physiological ro ute. Whether HOE490 has similar effect on the hepatic glucose disposal in the subjects with NIDDM, should be examined.