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This Article Full Text Full Text (PDF) All Versions of this Article: 288/6/G1135    most recent 00278.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Nielsen, M. F. Articles by Vilstrup, H. Search for Related Content PubMed PubMed Citation Articles by Nielsen, M. F. Articles by Vilstrup, H.

LIVER AND BILIARY TRACT

Contribution of defects in glucose uptake to carbohydrate intolerance in liver cirrhosis: assessment during physiological glucose and insulin concentrations

¹Department of Medicine V (Hepatology and Gastroenterology) and ⁴Departments of Medicine M (Endocrinology and Metabolism) and Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark; ²Metabolism and Nutrition Unit, San Raffaele Scientific Institute, Milan, Italy; and ³Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio

Submitted 29 June 2004 ; accepted in final form 1 January 2005

It is well established that subjects with liver cirrhosis are insulin resistant, but the contribution of defects in insulin secretion and/or action to glucose intolerance remains unresolved. Healthy individuals and subjects with liver cirrhosis were studied on two occasions: 1) an oral glucose tolerance test was performed, and 2) insulin secretion was inhibited and glucose was infused in a pattern and amount mimicking the systemic delivery rate of glucose after a carbohydrate meal. Insulin was concurrently infused to mimic a healthy postprandial insulin profile. Postabsorptive glucose concentrations were equal (5.36 ± 0.12 vs. 5.40 ± 0.25 mmol/l, P = 0.89), despite higher insulin (P < 0.01), C-peptide (P < 0.01), and free fatty acid (P = 0.05) concentrations in cirrhotic than in control subjects. Endogenous glucose release (EGR; 11.50 ± 0.50 vs. 11.73 ± 1.00 µmol·kg^–1·min^–1, P = 0.84) and the contribution of gluconeogenesis to EGR (6.60 ± 0.47 vs. 6.28 ± 0.64 µmol·kg^–1·min^–1, P = 0.70) were unaltered by cirrhosis. A minimal model recently developed for the oral glucose tolerance test demonstrated an impaired insulin sensitivity index (P < 0.05), whereas the -cell response to glucose was unaltered (P = 0.72). During prandial glucose and insulin infusions, the integrated glycemic response was greater in cirrhotic than in control subjects (P < 0.05). EGR decreased promptly and comparably in both groups, but glucose disappearance was insufficient at the prevailing glucose concentration (P < 0.05). Moreover, identical rates of [3-³H]glucose infusion produced higher tracer concentrations in cirrhotic than in control subjects (P < 0.05), implying a defect in glucose uptake. In conclusion, carbohydrate intolerance in liver cirrhosis is determined by insulin resistance and the ability of glucose to stimulate insulin secretion. During prandial glucose and insulin concentrations, EGR suppression was unaltered, but glucose uptake was impaired, which demonstrates that intolerance can be ascribed to a defect in glucose uptake, rather than abnormalities in glucose production or -cell function. Although insulin secretion ameliorates glucose intolerance, impaired glucose uptake during physiological glucose and insulin concentrations produces marked and sustained hyperglycemia, despite concurrent abnormalities in glucose production or insulin secretion.

insulin action; minimal model; gluconeogenesis