EFFECTS OF INSULIN-LIKE-GROWTH-FACTOR-I ON GLUCOSE-METABOLISM IN RATSWITH LIVER-CIRRHOSIS

To determine the effect of insulinlike growth factor I (IGF-I) on gluc ose metabolism in cirrhosis, a 2-h euglycemic clamp with IGF-I (0.65 n mol.kg(-1) min(-1)) or insulin (12 pmol.kg(-1).min(-1)) was performed in awake rats with carbon tetrachloride-induced liver cirrhosis. Rates of [3-H-3]glucose-determined whole body glucose turnover were similar in the fasting state in cirrhotic and control rats (36.4 +/- 2.6 and 37.7 +/- 2.8 mu mol.kg(-1) min(-1), respectively). In the control grou p, IGF-I and insulin had similar effects on turnover (81.6 +/- 27.0 an d 76.1 +/- 9.9 mu mol.kg(-1).min(-1)), muscle glycogen synthesis (47.5 +/- 12.3 and 37.5 +/- 2.5 nmol.g muscle(-1).min(-1)), and suppression of endogenous glucose production (EGP; -54 +/- 14 and -60 +/- 12%). C irrhotic rats were markedly insulin resistant, reflected by a 43% redu ction of turnover (43.8 +/- 9.4 mu mol.g muscle(-1).min(-1); P = 0.03) , a 73% reduction in muscle glycogen synthesis (10.2 +/- 3.4 nmol.g mu scle(-1).min(-1); P < 0.0001), and a diminished suppression of EGP (-3 2 +/- 17% vs. control: -56 +/- 14%; P < 0.05). In contrast, during the IGF-I clamps, turnover increased threefold in the cirrhotic rats (P = 0.001), rates of muscle glycogen synthesis were 7.4 times higher than during the insulin stimulation (P < 0.0001), and EGP was suppressed b y 80 +/- 12% (P < 0.05). In conclusion, insulin resistance in cirrhoti c rats is mostly due to defects in insulin-stimulated muscle glycogen synthesis, and the ability of IGF-I to stimulate muscle glycogen synth esis as well as suppress EGP is maintained in cirrhotic rats. These fi ndings suggest that alterations in both hepatic and peripheral glucose metabolism in patients with cirrhosis might be amenable to IGF-I ther apy.