J. Endocrinol. Invest. 14.727-735, 1991 In vivo insulin action in hepatocellular and cholestatic liver cirrhosis N. Barzilai*, P. Cohen*, E. Karnieli*, R. Enat*, O. Epstein**, J. Owen** and N. Mclntyre** *Metabolic Unit, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel and **Academic Department of Medicine, Royal Free Hospital and School of Medicine, London, NW3 2QG, United Kingdom ABSTRACT. The in vivo dose response curve to in- sulin were studied, using an euglycemic insulin clamp technique, in 13 cirrhotic patients [8 with "hepatocellular" (HC) (nonalcoholics) and 5 with "cholestatic" (CHOL) cirrhosis] and 12 healthy con- trols (N). Subjects were studied in the basal state and during infusion of insulin at 3 different rates - 1, 3, 10 mU kg- 1 min- 1 . Insulin responsiveness was similar in N and in HC, but it was 23% greater in CHOL (p < 0.001). Insulin sensitivity was decreased in cir- rhotics as compared with N but this difference was only significant (p < 0.001 ) in HC. (ED50:62 + 5, 88 + 13 and 136 + 16 Ilu ml- 1 in N, CHOL and HC respectively). Insulin clearance rate (ICR) was sig- nificantly (p < 0.005) decreased in HC (1060 ± 80, INTRODUCTION Cirrhosis of the liver is often associated with marked intolerance to oral glucose while intravenous glu- cose tolerance is less affected; sometimes overt di- abetes mellitus is present (1-3). The evidence that glucose intolerance in cirrhosis is due to resistance to endogenous insulin is con- vincing. In cirrhotics a high plasma insulin occurs with normal fasting blood glucose, and the insulin response to oral glucose is exaggerated (1, 2, 4, 5,); there is a diminished hypoglycemic response to exogenous insulin (2, 6). These findings and those from studies involving infusion of glucose, insulin and somatostatin (7), and one-point insulin clamp techniques (8, 9), all suggest insulin resistance in cirrhosis. Insulin resistance also explains the greater impairment of oral than intravenous glucose tolerance in cirrhosis as insulin plays a more im- Key-words. Glucose. insulin. insulin resistance, hepatocellular cirrhosis. cholestatic cirrhosis. Correspondence: Nir Barzilai, MD., Division of Endocrinology. Department of Medicine. The New York Hospital. Cornell Medical Center. 525 East 68th Street, New York, NY 10021, USA Received June 18. 1990; accepted April 15. 1991. 727 996 ± 95 and 776 ± 128 ml sq m- 1 ml- 1 in N, CHOL and HC respectively. Basal hepatic glucose pro- duction (BHGP) was 39% lower in HC (p < 0.005) and 24% lower in CHOL (p < 0.05) than in N. Erythrocyte cholesterol phospholipid ratio was sig- nificantly elevated (p < 0.001 ) in both groups of cir- rhotic patients but was not correlated to specific metabolic changes described. In summary: i) inter- variations in insulin dependent glucose metabolism were described in different cirrhotic groups; ii) basal hepatic glucose production and insulin clearance rate impaired in the different groups of cirrhotics; iii) the role of decreased cholesterol/phospholipid ratio on tissues glucose metabolism in cirrhotic pa- tients should be further studied. portant role in the disposal of an oral glucose load (10). The reasons for hyperinsulinemia and insulin resis- tance in liver disease are unclear. Studies of hy- perinsulinemia using the insulin/C-peptide ratio have given equivocal results, suggesting increased insulin secretion (11), decreased clearance (12, 13), or that both mechanisms playa part (3, 14). In direct catheterization studies hepatic insulin ex- traction in alcoholic cirrhotics was less than half that in normals (15). Studies using 3 or 4 point insulin clamp techniques have been performed, mainly on alcoholic cirrhotics, to assess whether insulin re- sistance is due to decreased glucose utilization by peripheral tissues in response to insulin (16). They suggested both decreased "sensitivity" and de- creased "responsiveness", i.e., defects at both the insulin receptor and at post-receptor sites (17-19). In these studies no distinction was made between sub-populations of cirrhotic patients and only one study, using a single insulin infusion rate, investi- gated patients with "cholestatic" cirrhosis such as primary biliary cirrhosis (20). This may be relevant as cholestatic rats appear to have enhanced rather than reduced glucose removal (21). The mechanism for altered insulin sensitivity and