Control of Hepatic Glucose Metabolism by the Oral Hypoglycemic Sulfonylureas.

摘要

The oral hypoglycemic sulfonylureas are widely used in the treatment of noninsulin-dependent diabetes mellitus. Although these drugs acutely stimulate insulin secretion from the pancreas, upon chronic administration blood Insulin concentrations return to pretreatment levels, while hypoglycemia persists. This suggests that these drugs might have extrapancreatic hypoglycemic actions. The important role of the liver In glucoregulation Implies that this organ might be a target tissue for the sulfonylureas. In fact, several studies have suggested that these drugs alter hepatic carbohydrate metabolism, although a direct inhibition of hepatic glucose output has not been demonstrated. The present study was conducted to investigate the direct actions of the sulfonylureas on: 1) glucose output; 2) glycogenaccumulation; 3) levels of gluconeogenic intermediates; and 4) activities of glycogen metabolizing enzymes In Isolated rat hepatocytes. Hepatocytes were Isolated by collagenase digestion from male, Sprague-Dawley rats and incubated In Krebs-Henseleit-HEPES buffer in the presence of either 30 mM glucose; or 10 mM glucose, 5 mM lactate, 5 mM glutamine, and Minimal Essential Medium amino acid mixture. Hepatocyte glycogen content was measured after precipitation of glycogen with 66% ethanol and conversion to glucose. Glucose output was assessed by measuring incorporation of [14C]-lactate into [14C]-glucose.Labelled compounds were separated by ion-exchange chromatography in deproteinized samples. Activities of glycogen metabolizing enzymes were assayed In homogenates of hepatocytes by measuring incorporation of [14C]-uridine diphosphoglucose (for synthase) and Incorporation of [14C]-glucose 1-phosphate (for phosphorylase) into glycogen. Radiolabelled substrates were separated from radiolabelled glycogen by ion exchange chromatography.