Novel glimepiride derivatives with potential as double-edged swords against type II diabetes

Abstract

Sulphonylurea drugs have been widely used in the safe and efficacous therapy of type II diabetes during the past five decades. They lower blood glucose predominantly via the stimulation of insulin release from pancreatic beta-cells. However, a moderate insulin-independent regulation of fatty acid esterification and release in adipose tissue cells has been reported for certain sulphonylureas, in particular for glimepiride. On basis of the known pleiotropic pathogenesis of type II diabetes with a combination of beta-cell failure and peripheral, including adipocyte, insulin resistance, anti-diabetic drugs exerting both insulin releasing- and fatty acid-metabolizing activities in a more balanced and potent fashion may be of advantage. However, the completely different molecular mechanisms underlying the insulin-releasing and fatty acid-metabolizing activities, as have been delineated so far for glimepiride, may hamper their optimization within a single sulphonylurea molecule. By analyzing conventional sulphonylureas and novel glimepiride derivatives for their activities at the primary targets and downstream steps in both beta-cells and adipocytes in vitro we demonstrate here that the insulin-releasing and fatty acid-metabolizing activities are critically dependent on both overlapping and independent structural determinants. These were unravelled by the parallel losses of these two activities in a subset of glimepiride derivatives and the impairment in the insulin-releasing activity in parallel with elevation in the fatty acid-metabolizing activity in a different subset. Together these findings may provide a basis for the design of novel sulphonylureas with blood glucose-lowering activity relying on less pronounced stimulation of insulin release from pancreatic beta-cells and more pronounced insulin-independent stimulation of esterification as well as inhibition of release of fatty acids by adipocytes than provoked by the sulphonylureas currently used in therapy.