Effects of insulin-like growth factor-i on glucose metabolism in
rats with liver cirrhosis.
Petersen, Kitt Falk, Ralph Jacob, A. Brian West, Robert S. Sherwin,
and Gerald I. Shulman.
Departments of Internal Medicine and Pathology, Yale University
School of Medicine, New Haven, CT
APStracts 4:0193E, 1997.
To determine the effect of insulin-like growth factor-I (IGF-I) on
glucose metabolism in rats with liver cirrhosis, awake Sprague-Dawley
rats, with carbon tetrachloride (CCl4) induced liver cirrhosis, were
given a two hour infusion of IGF-I (0.65 nmol/(kg-min)) or a dose of
insulin with similar effectiveness (12 pmol/(kg-min)) while
maintaining euglycemia. Rates of hepatic glucose production were
assessed by a [3-3H]glucose infusion and were similar in the fasting
state in the cirrhotic (36.4+/-2.6 [mu]mol/(kg-min), n=16) and the
age matched, untreated control rats (37.7+/-2.8 [mu]mol/(kg-min),
n=14). In the control group, IGF-I and insulin had similar
stimulating effects on rates of a) whole body glucose uptake (IGF-I:
81.6+/-27.0 [mu]mol/(kg-min), n=8, insulin: 76.1+/-9.9 [mu]mol/(kg
-min), n=6), b) muscle glycogen synthesis (IGF-I: 47.5+/-12.3 nmol/(g
muscle-min), insulin: 37.5+/-2.5 nmol/(g muscle-min)) and suppression
of hepatic glucose production (IGF-I: 54+/-14%, insulin: 60+/-12%).
Cirrhotic rats were markedly insulin resistant as reflected by a 42%
reduction in the rates of insulin stimulated whole body glucose
uptake (43.8+/-9.4 [mu]mol/(kg-min) (n=7); P=0.03 vs. control), a 73%
reduction in rates of muscle glycogen synthesis (10.2+/-3.4 nmol/(g
muscle-min); P<0.0001 vs. control), and a 43% diminution in the
suppression of hepatic glucose production (32+/-17% vs. control:
56+/-14%; P<0.05). In contrast, during the IGF-I glucose clamp
studies rates of whole body glucose uptake increased threefold in the
cirrhotic rats (106.4+/-41.5 [mu]mol/(kg-min) (n=9); P=0.001 vs.
insulin, P=0.232 vs. control+IGF-I), rates of muscle glycogen
synthesis were 7.4 times higher than during the insulin stimulation
(75.4+/-28.0 nmol/(g muscle-min); P<0.0001 vs. insulin, P=0.08 vs.
control+IGF-I) and hepatic glucose production was suppressed by 80+/
-12%; (P<0.05 vs. insulin, P=0.292 vs. control+IGF-I). In
conclusion, cirrhotic rats are markedly insulin resistant 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 hepatic glucose production 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.
Received 4 June 1997; accepted in final form 21 August 1997.
APS Manuscript Number E260-7.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 5 September 1997