Insulin resistance is a characteristic feature of glucose-intolerant and diabetic cirrhotic patients. The pathogenic factors, however, that are responsible for the development of impaired glucose tolerance in cirrhosis, remain unclear. To examine whether the ability of hyperglycemia per se to enhance glucose uptake (by means of mass-action effect) is impaired in cirrhosis, we measured (insulin-independent) wholebody glucose disposal during hyperglycemia (hyperglycemic clamp studies, +125 mg/dl, in combination with an infusion of somatostatin (500 p a r ) , insulin (0.1 mU/kg min) and glucagon (0.5 ng/kg min) to "clamp" hormone levels at baseline), whole-body glucose oxidation (indirect calorimetry) and glucose turnover (prime-continuous infusion of [6,6-'H,-]glucose in a clinically homogenous group of cirrhotic patients with glucose intolerance (n = 7 ) or frank diabetes mellitus (n = 7) and in control individuals (n = 7). Fasting plasma glucose concentrations were normal in glucose-intolerant patients but were significantly increased in diabetic patients (158 & 19 vs. 87 2 2 mg/dl in controls; p < 0.01). Plasma glucose concentrations were clamped at 214 & 4 mg/dl in controls, at 212 * 4 mg/dl in glucose-intolerant patients and at 287 2 19 mg/dl in diabetic patients; plasma insulin and glucagon concentrations were maintained at baseline levels. In the basal state, total-body glucose disposal (which equals basal hepatic glucose output) was normal in glucose-intolerant patients (2.25 2 0.11 mgkg min) but was increased in diabetic patients compared with controls (3.32 * 0.26 mg/dl vs. 2.45 * 0.10 mg/dl; p < 0.01). Hyperglycemia significantly stimulated whole-body glucose uptake in glucose-intolerant cirrhotic patients ( + 0.97 f 0.23 mg/kg/min; p < 0.01 vs. baseline), similar to control values (+1.18 .+ 0.26; p < 0.01 vs. baseline). In controls and glucose-intolerant patients, stimulation of glucose oxidation and nonoxidative glucose disposal were respon-