Effect of misoprostol (PGE1) on glucose metabolism in type-2-diabetic and control subjects N. A. Lee, M. Matsuda, P. Bressler, T. Pratipanawatr, L. Glass, L. J. Mandarino and R. A. DeFronzo Diabetes Division, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA In vitro and in vivo studies have demonstrated that prostaglandins of the E series enhance muscle glucose uptake. We examined the effect of acute misoprostol (PGE1) administration on whole body insulin-mediated glucose disposal, as well as the major intracellular pathways of glucose metabolism in type 2 diabetic (n  10) and non-diabetic (n  4) subjects. Each subject received two 240-min euglycaemic insulin (40 mU/m 2 /min) clamp studies with tritiated glucose and indirect calorimetry. During one of the insulin clamp studies, 200 mg of misoprostol was ingested at 90 and 150min after the start of the insulin infusion. Insulin-mediated total body glucose disposal, glycolysis, glycogenesis and glucose oxidation were similar during the insulin clamp studies performed without and with misoprostol in both the diabetic and non-diabetic groups. These results demonstrate that the acute administration of misoprostol does not enhance insulin-mediated glucose disposal in either type-2-diabetic or non-diabetic subjects. Keywords: type 2 diabetes mellitus, insulin resistance, glucose metabolism, misoprostol (PGE1), prostglandin E1 Received 7 July 2001; returned for revision 9 July 2001; revised version accepted 31 July 2001 Background Prostaglandins are naturally occurring, vasodilatory hormones that have been shown to influence blood flow to a variety of organs, including muscle [1]. Recent studies by Baron [2] have demonstrated that the action of insulin to promote glucose metabolism in skeletal muscle is dependent upon two components: (i) an increase in muscle blood flow; and (ii) a direct cellular action of the hormone to enhance glucose transport and intracellular glucose metabolism. In insulin-resistant states, including obesity and type 2 diabetes mellitus, the ability of insulin to increase muscle blood flow [2] and to stimulate muscle glucose metabolism [3,4] is impaired. Prostaglandins are important regulators of muscle blood flow [1,5] and in vitro studies have shown that prostaglandins of the E series exert a direct stimulatory effect on muscle glucose uptake, glycolysis and glycogen synthesis [6±9]. PGE1 and PGE2 also increase glucose transport and glycogen synthesis in adipocytes [10] and hepatocytes [11]. It is noteworthy that addition of insulin to the perfused rat hindlimb enhances glucose transport and increases the release of PGE 2 and PGF 2 a [12]. Physiological concentrations of insulin also augment prostaglandin synthesis in cardiac [13] and skeletal [14] muscle. In vivo, Wicklmayr et al. [15], Dietze and Wicklmayr [16] and Dietze et al. [17] have shown that acute PGE 1 infusion into the human forearm increases muscle glucose uptake, both augment- ing blood flow and widening the arterio-venous glucose concentration difference. Several investigators have reported that oral synthetic analogues of PGE1 and PGE2 reduce the fasting [18,19] and post-prandial [20] plasma glucose concentrations in type-2-diabetic subjects, although these salutory effects on glucose tended to wane with time. Taken collectively, these observations suggest that prostaglandins, either via direct cellular effects or by enhanced tissue blood flow, may play an important role in the regulation of muscle Correspondence: Ralph A. DeFronzo MD, Diabetes Division, 7703 Floyd Curl Drive, University of Texas Health Science Center, San Antonio, TX 78229, USA ORIGINAL ARTICLE # 2002 Blackwell Science Ltd Diabetes, Obesity and Metabolism, 4, 2002, 195±200 195