PATHOGENESIS OF GLUCOSE-INTOLERANCE AND DIABETES-MELLITUS IN CIRRHOSIS

Glucose intolerance and diabetes mellitus are both prevalent in cirrho sis, yet the pathogenesis of impaired glucose metabolism remains unkno wn. Therefore insulin secretion (hyperglycemic clamp, +125 mg/dl), ins ulin sensitivity (euglycemic hyperinsulinemic insulin clamp, + 10 mu U /ml and +50 mu U/ml), whole-body glucose oxidation (indirect calorimet ry) and glucose turnover ([6,6-H-2(2)]glucose isotope dilution) were e valuated in a homogenous group of cirrhotic patients with glucose into lerance (n = 7) or frank diabetes mellitus (n = 6). The results were c ompared with those obtained in control subjects (n = 8). In glucose-in tolerant patients, whole-body glucose uptake (mainly reflecting glucos e utilization by muscle) was significantly impaired in patients during both insulin infusions as a result of decreased stimulation of the tw o major intracellular pathways of glucose disposal-nonoxidative glucos e disposal (i.e., glycogen synthesis) and glucose oxidation. Hepatic g lucose production was normal in the basal state and was normally suppr essed during stepwise insulin infusion (by 65% and 85%, respectively, p = NS vs. controls). Hyperglycemia-induced increases of plasma C-pept ide concentrations were comparable to those in controls (p = NS). In d iabetic patients, insulin-mediated glucose uptake was significantly re duced, mainly because of impaired non-oxidative glucose disposal. Gluc ose oxidation appeared to be reduced, too. Hepatic glucose production was significantly increased in the basal state (3.03 +/- 0.24 vs. 2.34 +/- 0.10 mg/kg min, p < 0.02) and during insulin infusion (+50 mu U/m l: 0.67 +/- 0.17 vs. 0.13 +/- 0.08 mg/kg min, p < 0.05) compared with that in controls. Both the first and second phases of beta-cell secret ion were significantly reduced in response to steady-state hyperglycem ia (both p < 0.02 vs. control values). In conclusion, glucose intolera nce in cirrhosis results from two abnormalities that occur simultaneou sly: (a) insulin resistance of muscle and (b) an inadequate response ( even when comparable to that of controls) of the beta-cells to appropr iately secrete insulin to overcome the defect in insulin action. Diabe tes mellitus in insulin resistant cirrhotic patients develops as the r esult of progressive impairment in insulin secretion together with the development of hepatic insulin resistance leading to fasting hypergly cemia and a diabetic glucose tolerance profile.