Lipid metabolism and insulin resistance in cirrhosis

Fasting patients with cirrhosis have high plasma non-esterified fatty acids, and a high turnover and oxidation of non-esterified fatty acids, despite high plasma insulin levels. To assess whether increased non-esterified fatty acid availability impairs utilisation of circulating glucose, and contributes to the insulin insensitivity in cirrhosis, we measured glucose, non-esterified fatty acid and glycerol flux rates, in patients with cirrhosis and controls, in the basal state and during a 0.05 U.kg-1.h-1 hyperinsulinaemic euglycaemic clamp. After an overnight fast, basal blood glucose and glucose turnover were similar in both groups. Basal plasma glycerol and non-esterified fatty acid levels were higher in patients with cirrhosis as were 1-14C-nonesterified fatty acid turnover (4.48 +/- 0.53 vs 2.54 +/- 0.45 mumol.kg-1.min-1, p < 0.05) and 2H5-glycerol turnover (3.27 +/- 0.34 vs 2.24 +/- 0.15 mumol.kg-1.min-1, p < 0.05), indicating increased lipolysis in patients with cirrhosis; metabolic clearance rate of non-esterified fatty acids and glycerol were similar in both groups, suggesting no impairment of tissue uptake in patients. The euglycaemic clamp showed patients with cirrhosis to be markedly insensitive to insulin. The glucose metabolic clearance rate increased during the clamp in controls (p < 0.005) but not in patients with cirrhosis, indicating that infused insulin had little or no effect on glucose disposal in the patients. Clamp glucose turnover in controls was higher than in the basal state (p < 0.001); in patients with cirrhosis it was lower. The profound insulin insensitivity and the clamping of blood glucose below fasting levels explains the fall in glucose turnover in patients with cirrhosis during the clamp. In both groups serum non-esterified fatty acid and glycerol levels, and their appearance rates, were suppressed during the clamp, but levels remained significantly higher in patients with cirrhosis (non-esterified fatty acids, 0.20 +/- 0.4 vs 0.10 +/- 0.01 mmol/l, p < 0.05; glycerol 74 +/- 9 vs 46 +/- 4 mumol/l, p < 0.05). This, with the high basal non-esterified fatty acid and glycerol levels seen in patients with cirrhosis, despite high insulin levels, suggests resistance of adipose tissue lipolysis to insulin. There was no correlation between glucose infusion requirements and non-esterified fatty acid turnover. The normal turnover of blood glucose in fasting patients with cirrhosis, despite increased non-esterified fatty acid turnover, suggests utilisation mainly by tissues with an obligatory requirement for glucose, which may be similar in patients with cirrhosis and controls.(ABSTRACT TRUNCATED AT 400 WORDS)