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J Biol Chem, Vol. 273, Issue 28, 17771-17779, July 10, 1998
From the Departments of Internal Medicine and Pharmacology, Gifford
Laboratories for Diabetes Research, University of Texas Southwestern
Medical Center, Dallas, Texas 75235-8854 and the Nutrients and certain growth factors stimulate
pancreatic
Insulin-like Growth Factor I (IGF-I)-stimulated Pancreatic
-Cell Growth Is Glucose-dependent
SYNERGISTIC ACTIVATION OF INSULIN RECEPTOR SUBSTRATE-MEDIATED
SIGNAL TRANSDUCTION PATHWAYS BY GLUCOSE AND IGF-I IN INS-1 CELLS
, and Research
Division, Joslin Diabetes Center, Harvard Medical School,
Boston, Massachusetts 02215
-cell mitogenesis, however, the appropriate mitogenic
signal transduction pathways have not been defined. In the
glucose-sensitive pancreatic -cell line, INS-1, it was found that
glucose (6-18 mM) independently increased INS-1 cell
proliferation (>20-fold at 15 mM glucose). Insulin-like
growth factor I (IGF-I)-induced INS-1 cell proliferation was
glucose-dependent only in the physiologically relevant concentration range (6-18 mM glucose). The combination of IGF-I and
glucose was synergistic, increasing INS-1 cell proliferation >50-fold at 15 mM glucose + 10 nM IGF-I. Glucose
metabolism and phosphatidylinositol 3'-kinase (PI 3'-kinase) activation
were necessary for both glucose and IGF-I-stimulated INS-1 cell
proliferation. IGF-I and 15 mM glucose increased tyrosine
phosphorylation mediated recruitment of Grb2/mSOS and PI 3'-kinase to
IRS-2 and pp60. Glucose and IGF-I also induced Shc association with
Grb2/mSOS. Glucose (3-18 mM) and IGF-I, independently of
glucose, activated mitogen-activated protein kinase but this did not
correlate with IGF-I-induced -cell proliferation. In contrast,
p70S6K was activated with increasing glucose concentration
(between 6 and 18 mM), and potentiated by IGF-I in the same
glucose concentration range which correlated with INS-1 cell
proliferation rate. Thus, glucose and IGF-I-induced -cell
proliferation were mediated via a signaling mechanism that was
facilitated by mitogen-activated protein kinase but dependent on
IRS-mediated induction of PI 3'-kinase activity and downstream
activation of p70S6K. The glucose dependence of IGF-I
mediated INS-1 cell proliferation emphasizes -cell signaling
mechanisms are rather unique in being tightly linked to glycolytic
metabolic flux.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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