TY - JOUR
T1 - Contribution of defects in glucose uptake to carbohydrate intolerance in liver cirrhosis
T2 - Assessment during physiological glucose and insulin concentrations
AU - Nielsen, Michael F.
AU - Caumo, Andrea
AU - Aagaard, Niels Kristian
AU - Chandramouli, Visvanathan
AU - Schumann, William C.
AU - Landau, Bernard R.
AU - Schmitz, Ole
AU - Vilstrup, Hendrik
PY - 2005/6
Y1 - 2005/6
N2 - 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 β-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 β-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.
AB - 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 β-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 β-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.
KW - Gluconeogenesis
KW - Insulin action
KW - Minimal model
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U2 - 10.1152/ajpgi.00278.2004
DO - 10.1152/ajpgi.00278.2004
M3 - Article
C2 - 15637182
AN - SCOPUS:19644376383
VL - 288
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6119
IS - 6 51-6
ER -