GLP-l effectively reverts insulin resistance in rats with CCL 4-induced liver cirrhosis

Abstract

Introduction: Insulin resistance is a characteristic feature of patients with liver cirrhosis. To characterize and quantify the extent as well as the site of impaired glucose utilization and to elucidate the possible potency of GLP-l to revert the impaired glucose utilization, both healthy and cirrhotic rats underwent euglycemic hyperinsulinemic damp studies. Methods: In male Lewis rats, liver cirrhosis was induced by inhalation of CCI4 for 10 weeks and phenobarbital (PB)-enriched drinking water. Using the euglycemic hyperinsulinemic clamp technique coupled with isotopic measurements of glucose uptake in individual tissues, insulin action was studied in the presence and absence of 3.0 pmol GLP-l/kgBW/min during clamping. Clamp studies were performed by continuous insulin infusion in doses ranging from 1 to 10 nmol/kg BW/h. Blood samples were obtained and glucose infusion was adjusted accordingly to maintain euglycemia allowing determination of insulin action on whole body glucose disposal. During euglycemia, insulin action on individual tissues was measured with 2-deoxy-D-[1-3H]glucose and [U-1 Results: After 10 weeks, a CCli PB-induced and histologically-validated liver cirrhosis was found in 98 % of treated rats. In cirrhotic rats, glucose utilization was impaired and resulted in a significant reduction of total body glucose disposal by 30 %. In these animals, glycogen formation was significantly reduced in the diaphragm and red skeletal muscle. Administration of GLP-I fully reverted the impaired glucose utilization. Conclusion: In rats with a CCI4/PBinduced liver cirrhosis, insulin resistance is predominantly marked by an impaired glucose utilization located in the diaphragm and red skeletal muscle which can be completely reverted by GLP-l. These results stress the potential pharmacological properties of GLP-l in the treatment of NIDDM in humans.