In animal models, conflicting results on the effect of occur in as many as 10% to 15% of cirrhotic patients. 2,3 cirrhosis on glucose metabolism have been reported. Furthermore, the majority of nondiabetic cirrhotic indi-The use of various toxins as well as differences in experividuals are characterized by hyperinsulinemia in the mental protocols may be responsible for these controfasting state 4,5 and excessive insulin response to an versial data. However, differences may also be explained oral or intravenous glucose load. 6,7 Insulin resistance by the fact that glucose metabolism has been evaluated thus appears as the main feature of glucose metabolism following different time intervals after cessation of the in human cirrhosis. 8,9 It is well accepted that hepatic toxic injury. Therefore, we have performed intravenous insulin sensitivity is maintained in cirrhosis, 7,10 and glucose tolerance tests, euglycemic hyperinsulinemic that the main site of insulin resistance in human circlamps (at 2, 6, and 30 mU/kgrmin insulin infusion rates), rhosis is skeletal muscle (decreased glycogen syntheand determination of peripheral tissue glucose metabolic index (by [ 3 H]2-deoxy-glucose injection) in rats sis), although other tissues such as the white adipose treated for 10 weeks with carbon tetrachloride, either 3 tissue may also play a significant role in other diseases days (acute group) or 2 weeks (delayed group) after the and species. At the cellular level, insulin resistance last CCl 4 dose was administered. Cirrhosis was conmost likely involves a postreceptor defect, 2,8 but the firmed by liver histological analysis, and by a 22% (P exact nature of this defect remains unknown. õ .05) decrease in 13 C-aminopyrine demethylation. In the Although studies based on human subjects are likely acute group, whole-body glucose disposal was decreased to give the most relevant information, animal models at the highest insulin infusion rate only (19.7 { 1.2 vs. of cirrhosis are still clearly needed to investigate in 23.4 { 1.2 mg/kgrmin in controls, P õ .05). In contrast, more detail the mechanisms of impairment in glucose results of the delayed group were not different from conmetabolism. Although animal models of cirrhosis are trols at any insulin infusion rate. Peripheral tissue glu-
scarce and often unreliable, 11 many attempts have been cose metabolic index was significantly decreased in all muscles tested in the acute group compared with con-made in the past to study metabolic alterations of cirtrols. A significant decrease of glucose utilization was rhosis using animal models obtained with various toxfound in some but not all muscles in the delayed group ins administered by many different routes and followbut was less pronounced than in the acute group. In ing variable schedules. [12][13][14][15] Many conflicting results conclusion, this study showed that insulin sensitivity in have been reported, depending on the toxin used to cirrhotic rats is time-dependent with regard to the last induce cirrhosis, and the delay observed between the CCl 4 administration. These results must be taken into end of induction treatment and the metabolic experiaccount when using this experimental model of liver cirmentations. In recent years, the most popular model rhosis. (HEPATOLOGY 1996;23:582-588.) has been the carbon tetrachloride-induced cirrhosis in rats. [14][15][16] Although this model has already been used Glucose intolerance in liver disease was recognized for metabolic studies, 15,17,18 no attempt has been made as far back as 1906, when Naunyn 1 coined the term so far to clearly evaluate the influence of CCl 4 toxicity ''hepatogenous diabetes.'' In the clinical setting, glucose on glucose metabolism, and thus the relevance of this homeostasis is often impaired; diabetes mellitus may model to the study of the mechanisms of insulin resistance in human cirrhosis.
After a careful evaluation of morphologic and metabolic criteria needed to confirm the presence of cirrhosis Abbreviations: ABT, aminopyrine breath test; GIR, glucose infusion rate; WAT, white adipose tissue; IBAT, interscapular brown adipose tissue.
after chronic phenobarbital and CCl 4 treatment, we ex-From the Laboratoire de Physiologie and Unite ´de Recherche Associe ´e, amined the following in this study: (1) glucose tolerance Centre National de Recherche Scientifique D1341, Universite ´Claude Bernard by intravenous glucose tolerance tests; (2) whole-body