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We used a dual-isotope method (oral 11-_4C Iglucose and intravenous 16-3Hlglucose) to examine whether the oral glucose intolerance of cirrhosis is due to (a) a greater input of glucose into the systemic circulation (owing to a lower first-pass hepatic uptake of ingested glucose, or to impaired inhibition of hepatic glucose output), (b) a lower rate of glucose removal, or (c) a combination of these mechanisms. Indirect calorimetry was used to measure oxidative and nonoxidative metabolism.Basal plasma glucose levels (cirrhotics, 5.6±0.4[SE1, controls, 5.1±0.2 mmol/liter), and rates of glucose appearance (Ra) and disappearance (Rd) were similar in the two groups. After 75 g of oral glucose, plasma glucose levels were higher in cirrhotics than controls, the curves diverging for 80 min despite markedly higher insulin levels in cirrhotics. During the first 20 min, there was very little change in glucose Rd and the greater initial increase in plasma glucose in cirrhotics resulted from a higher Ra of ingested 11-_4Cjglucose into the systemic circulation, suggesting a reduced first-pass hepatic uptake of portal venous glucose. The continuing divergence of the plasma glucose curves was due to a lower glucose Rd between 30 and 80 min (cirrhotics 236±17 mg/kg in 50 min, controls 280±17 mg/kg in 50 min, P < 0.05, one-tailed test). Glucose metabolic clearance rate rose more slowly in cirrhotics and was significantly lower than in controls during the first 2 h after glucose ingestion (2.24±0.17 vs. 3.30±0.23 ml/kg per min, P < 0.005), in keeping with their known insulin insensitivity. Despite the higher initial glucose Ra in cirrhotics, during the entire 4-h period the quantity of total glucose and of ingested glucose (cirrhotics 54±2 g 172% of oral load], controls 54±3 g) appearing in the systemic circulation were similar. Overall glucose Rd (cirrhotics 72.5±3.8 g/4 h, controls 77.2±2.2 g/4 h) and percent suppression of hepatic glucose output over 4 h (cirrhotics, 53±10%, controls 49±8%) were also similar.After glucose ingestion much of the extra glucose utilized was oxidized to provide energy that in the basal state was derived from lipid fuels. Glucose oxidation after glucose ingestion was similar in both groups and accounted for approximately two-thirds of glucose Rd. The reduction in overall nonoxidative glucose disposal did not reach significance (21±5 vs. 29±3 g/4 h, 0.05 < P < 0.1). Although our data would be compatible Address reprint requests to Dr. Yolanta T. Kruszynska, University Department of Medicine, Royal Free Hospital, Pond Street, London NW3 2QG.Received for publication 3 October 1991 and in revisedform 4 August 1992. with an impairment of tissue glycogen deposition after oral glucose, glucose storage as glycogen probably plays a small part in overall glucose disposal.Our results suggest that the higher glucose levels seen in cirrhotics after oral glucose are due initially to an increase in the amount of ingested glucose appearing in the systemic circulation, and subsequently to an impairment in g...

Short- and long-term regulation of hepatic carbohydrate metabolism by insulin-like growth factor II was studied in primary cultures of adult rat hepatocytes and compared to the metabolic potency of insulin. Insulin-like growth factor II stimulated glycogen synthesis from [14C]glucose, uptake of [3H]aminoisobutyric acid and [14C]lactate formation from [14C]glucose up to three-fold. Basal glycogenolysis was inhibited to about 10%, and glucagon-activated glycogenolysis was blocked completely. The enzymatic activity of glucokinase and pyruvate kinase was induced two-fold, the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was antagonized. Compared to insulin, half-maximal responses required up to 50 times higher insulin-like growth factor II concentrations ranging from 10-20 nmol/l. A similar difference was observed for binding affinity of insulin-like growth factor II to the insulin receptor. The interaction with the insulin-like growth factor II/mannose 6-phosphate (IGF-II/Man-6-P) receptor was examined by studying 125I-insulin-like growth factor II binding and uptake of lysosomal enzymes. The affinity of insulin-like growth factor II to the IGF-II/Man-6-P receptor was considerably higher than for the insulin receptor. Antibodies against the IGF-II/Man-6-P receptor did not affect metabolic responses to insulin-like growth factor II, while binding to its receptor and the receptor-mediated endocytosis of arylsulphatase A were strongly inhibited. Thus, in adult rat liver insulin-like growth factor II appeared to exert metabolic actions not via interaction with its own receptor but through low affinity binding to hepatic insulin receptors.

The inhibitory profiles of okadaic acid, calyculin A, cyclosporin A, and W-7 indicate that phosphatases 1 and 2A play a relevant role in cAMP-mediated enzyme release, whereas phosphatases 1 and 2B are predominantly involved in IP3/Ca(2+)-dependent stimulus-secretion coupling. The calmodulin antagonist W-7 interferes at multiple steps of intracellular signal-transduction pathways.

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