thioacetamide and Insulin-Resistance

Insulin resistance (IR) is recognised as an aetiopathogenic factor for a variety of liver diseases. This study investigated the susceptibility of the liver to the toxic actions of thioacetamide (TA) in a rat model of IR, induced by feeding the rats a high-fructose diet (60 g/100 g) for 30 days.. Hepatic function and damage were assessed at 0 hour and at 6, 12, 24 and 36 hours after a sublethal dose of TA (300 mg/kg intraperitoneally) was administered.. After 30 days of fructose feeding, the rats showed IR, a decline in their liver antioxidant status and a rise in lipid peroxidation. Liver dysfunction in fructose-fed rats was evident from a rise in transaminase and total bilirubin, a decrease in the albumin/globulin ratio in plasma, a decrease in nitrite and arginase, and an increase in protein carbonyl and nitrosothiol content in the liver. Increased staining for the 3-nitrotyrosine antibody was observed in the fructose-fed rat livers as compared to the controls. TA (300 mg/kg) caused 80 percent mortality in fructose-fed rats within 48 hours, while no death occurred among the controls.. Fructose-fed rats suffered from liver dysfunction and damage. TA caused liver injury in both control and fructose-fed rats. Time-based studies showed that progressive liver injury occurred only in rats that were fructose-fed from 6, 12 and 24 hours after TA administration, with a peak at 36 hours. In control diet-fed rats, the extent of damage was maximal at 24 hours, and declined at 36 hours. Thus, the toxic effects of TA are potentiated due to compromised liver function in the setting of IR.

Topics: Albumins; Animals; Antioxidants; Arginase; Bilirubin; Cytochrome P-450 CYP2E1; Dietary Carbohydrates; Disease Models, Animal; Fructose; Insulin Resistance; Lipid Peroxidation; Liver Diseases; Liver Function Tests; Male; Nitrites; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Sweetening Agents; Thioacetamide

Free radicals are involved in the pathogenesis of acute liver injury induced by thioacetamide (TAA). We investigated the effects of S-adenosylmethionine (SAMe) combined with/without vitamins C and E on TAA-induced acute liver injury in rats. TAA was given intraperitoneally (200 mg kg-1). Antioxidant treatments (SAMe, 25 mg kg-1; vitamin C, 100 mg kg-1; vitamin E, 200 mg kg-1, intraperitoneal) were given 1 h later. Liver histology, enzymology, and ability to release hepatic insulin-sensitizing substance (HISS) were assessed. TAA caused liver tissue injury, increased liver enzymes, and decreased insulin sensitivity (p<0.01). Blockade of HISS release by atropine did not further decrease insulin sensitivity in rats with TAA insult, indicating that the decrease in insulin sensitivity was HISS dependent. Treatment with SAMe alone or vitamins C+E slightly improved liver histology but not the changes in liver enzymes and insulin sensitivity. Combined treatment with SAMe plus vitamins C+E greatly protected the liver from tissue injury, the increase in liver enzymes, and the decrease in insulin sensitivity. In conclusion, acute liver injury causes HISS-dependent insulin resistance (HDIR). There are synergistic antioxidative effects among the antioxidants, SAMe and vitamins C and E, that protect the liver from TAA-induced HDIR, suggesting that antioxidant treatment may best be done using a balanced "cocktail."

Topics: Animals; Antioxidants; Ascorbic Acid; Drug Combinations; Drug Synergism; Insulin Resistance; Liver; Male; Rats; Rats, Sprague-Dawley; S-Adenosylmethionine; Thioacetamide; Vitamin E

Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of 125I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t1/2) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers (P less than 0.001). Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance.

Topics: Animals; Blood Glucose; Glucagon; Growth Hormone; Half-Life; Insulin; Insulin Resistance; Liver; Liver Cirrhosis, Experimental; Liver Function Tests; Male; Rats; Thioacetamide