Effects of insulin-like growth factor I on glucose metabolism in rats with liver cirrhosis.
To determine the effect of insulin-like growth factor I (IGF-I) on glucose metabolism in cirrhosis, a 2-h euglycemic clamp with IGF-I (0.65 nmol.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 [3-3H]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 mumol.kg-1.min-1, respectively). In the control group, IGF-I and insulin had similar effects on turnover (81.6 +/- 27.0 and 76.1 +/- 9.9 mumol.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%). Cirrhotic rats were markedly insulin resistant, reflected by a 43% reduction of turnover (43.8 +/- 9.4 mumol.g muscle-1.min-1; P = 0.03), a 73% reduction in muscle glycogen synthesis (10.2 +/- 3.4 nmol.g muscle-1.min-1; P < 0.0001), and a diminished suppression of EGP (-32 +/- 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 by 80 +/- 12% (P < 0.05). In conclusion, insulin resistance in cirrhotic rats is mostly due to defects in insulin-stimulated muscle glycogen synthesis, and the ability of IGF-I to stimulate muscle glycogen synthesis as well as suppress EGP is maintained in cirrhotic rats. These findings suggest that alterations in both hepatic and peripheral glucose metabolism in patients with cirrhosis might be amenable to IGF-I therapy.
Petersen
K F
KF
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Jacob
R
R
West
A B
AB
Sherwin
R S
RS
Shulman
G I
GI
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000096:biosynthesis; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D006003:Glycogen; D005947:Glucose