EFFECT OF SUBCUTANEOUS ESCHERICHIA-COLI-INDUCED HYPERMETABOLIC SEPSISON HEPATIC GLUCONEOGENESIS AND ITS HORMONAL RESPONSIVENESS IN THE RAT

In hypermetabolic sepsis, gluconeogenesis is markedly elevated during fasting, and is manifested as an increased rate of glucose appearance (R(a)). The likely causes of such a change are alterations in 1) conce ntration of systemic hormones, 2) concentration of glucose precursors, especially lactate, 3) activity of the key enzymes of the pathway, an d 4) hormone receptors and/or transmembrane signalling mechanisms, inv olved in the hormonal regulation of the pathway. In this study, we inv estigated the importance of the latter two factors in the increase of gluconeogenesis during hypermetabolic sepsis. Rats were rendered septi c by repeated subcutaneous administration of live Escherichia coli. Th e livers were perfused in vitro in a nonrecirculating mode to measure the rate of gluconeogenesis from saturating concentrations of lactate (5 mM) or lactate (5 mM) + pyruvate (0.5 mM), and the response of gluc oneogenesis to vasopressin (VP, 0.1 and 1.0 nM), glucagon (Glc, 0.1 an d 1.0 nM), and prostaglandin (PG) F2alpha (5 muM). The rate of glucone ogenesis without precursor supply was approximately 20-30 mumoles/100 g b w/hr during the first 4-6 min of perfusion, followed by a continuo us decline to very low levels. Infusion of lactate (5 mM) or lactate ( 5 mM) + pyruvate (0.5 mM) increased glucose output, and maintained it at approximately 100-110 and approximately 130-140 mumoles/100 g b w/h r, respectively. VP, Glc, and PGF2alpha stimulated the rate of glucone ogenesis in a dose-dependent manner (VP and Glc). No differences were observed between control and septic rats using these stimuli. On the b asis of these data, we propose that the increased rate of gluconeogene sis associated with subcutaneous E. coli-induced hypermetabolic spesis is not due to changes in the maximal capacity of the pathway of gluco neogenesis, or in the response of the liver to gluconeogenic hormones. It seems likely that alterations in the hormonal milieu, associated w ith an increased substrate availability, play an important role in the augmented gluconeogenesis in hypermetabolic sepsis. (C) 1993 Wiley-Li ss, Inc.