Rj. Denver et Cs. Nicoll, PANCREATIC HORMONES DIFFERENTIALLY REGULATE INSULIN-LIKE GROWTH-FACTOR (IGF)-I AND IGF-BINDING PROTEIN-PRODUCTION BY PRIMARY RAT HEPATOCYTES, Journal of Endocrinology, 142(2), 1994, pp. 299-310
We investigated the influence of and interactions among pancreatic hor
mones on the secretion of insulin-like growth factor-I (IGF-I) and IGF
-binding proteins (IGFBPs) by treating primary hepatocytes from young
male Long-Evans rats with insulin or glucagon in combination with rat
GH (rGH). The concentration of IGF-I secreted into the medium was esti
mated by radioimmunoassay after formic acid-acetone cryoextraction, an
d secreted IGFBPs were analysed by Western ligand blot and immunoblot;
accumulation of IGF-I mRNA was analysed by Northern blot. Both insuli
n (0.1-100 nmol/l) and rGH (0.5, 5 and 50 pmol/l) produced a dose-depe
ndent stimulation of IGF-I secretion over a 24-h incubation period. In
contrast, glucagon (0.1-100 nmol/l) inhibited IGF-I production in a d
ose-related manner. Glucagon (10 nmol/l) also inhibited IGF-I secretio
n stimulated by rGH (5 pmol/l) and insulin (10 nmol/l). Northern blot
analysis of total RNA isolated from rat hepatocytes revealed that rGH
(5 pmol/l) elevated IGF-I mRNA levels, glucagon (10 nmol/l) alone had
no effect on this parameter, but glucagon significantly reduced IGF-I
transcript accumulation in response to rGH. IGFBPs secreted by rat hep
atocytes run in two molecular weight ranges on SDS-PAGE: similar to 25
kDa (IGFBP-4) and similar to 29-31 kDa (IGFBP-1 and -2); the predomin
ant hormonally regulated IGFBP was identified as IGFBP-1. Insulin prod
uced a dose-dependent inhibition of production of IGFBP-1, while gluca
gon was stimulatory; when given together at an equivalent concentratio
n (1 nmol/l), the effects of insulin were dominant to glucagon on IGFB
P-1. These observations provide support for significant opposite roles
for the pancreatic hormones, insulin and glucagon, in the regulation
of liver IGF-I and IGFBP-1 production. As the production of pancreatic
hormones is influenced by nutritional status, these polypeptides may
mediate the effects of changing nutritional state on the hormonal cont
rol of protein anabolism and glucose homeostasis by directly influenci
ng the circulating level of liver-derived IGF-I and its binding protei
ns.