Insulin and insulin-like growth factor-1 regulate hepatic insulinlike growth factor binding protein-3 by different mechanisms

被引:34
作者
Villafuerte, BC [1 ]
Zhang, WN [1 ]
Phillips, LS [1 ]
机构
[1] EMORY UNIV, SCH MED, DIV ENDOCRINOL & METAB, ATLANTA, GA 30322 USA
关键词
D O I
10.1210/me.10.6.622
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Insulin-dependent diabetes mellitus is associated with decreased levels of circulating insulin-like growth factor binding protein-3 (IGFBP-3), which are restored toward normal by treatment with insulin and/or infusion of insulin-like growth factor-I (IGF-I). To understand underlying mechanisms, we studied IGFBP-3 production in cocultures of parenchymal and nonparenchymal cells from the livers of normal rats. Release of IGFBP-3 was measured by ligand blotting and was increased 1.9- and 15-fold by 10(-8) and 10(-6) M insulin compared with 10(-10) M (P < 0.05 for 10(-6) vs. 10(-10) M). Expression of IGFBP-3 mRNA was increased concomitantly by 23 and 226% (P < 0.05 for 10(-6) M vs. 10(-10) M), consistent with regulation in part at pretranslational levels. To evaluate mRNA stability, transcription was inhibited with 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB): IGFBP-3 mRNA t1/2 was estimated at 13 h and 17 h with addition of 10(-6) M and 10(-10) M insulin, respectively, ruling out regulation at the level of mRNA turnover. IGFBP-3 gene transcription rates were evaluated by nuclear run-on assays and were increased 2.9-fold with the addition of 10(-6) M insulin, as compared with 10(-10) M insulin, comparable to stimulation of expression. Addition of IGF-I at 2.6 x 10(-8) M and 5.3 x 10(-8) M increased IGFBP-3 release by 5.2- and 8.2-fold (both P < 0.05 vs. no IGF-I], with concomitant increase in IGFBP-3 mRNA expression by 14- and 29-fold (both P < 0.05 vs. no IGF-I), suggesting regulation at a pretranslational level. further studies showed that IGF-I did not have a significant effect on transcription initiation rates but prolonged the apparent half-life of IGFBP-3 mRNA about 2-fold. Stimulation of IGFBP-3 via type 1 IGF-I receptors was evaluated by studies with [QAYL] IGF-I; the analog increased IGFBP-3 mRNA expression 220 +/- 27% above the level obtained without IGF-I (vs. 133 +/- 9% with wild type IGF-I, P < 0.05), suggesting involvement of receptor-mediated synthesis. Conclusion: Insulin stimulates IGFBP-3 gene transcription but provides proportionally greater increases in IGFBP-3 release, consistent with regulation at both transcriptional and posttranslational levels; in contrast, IGF-I alters IGFBP-3 expression by decreasing IGFBP-3 mRNA degradation, consistent with regulation at pretranslational and posttranscriptional levels. Decreased IGFBP-3 levels in conditions of diabetes mellitus may be due to decreased hepatic IGFBP-3 release, and secondary both to decreased gene transcription (caused by insulin deficiency), as well as to decreased IGFBP-3 mRNA half-life (caused by low levels of IGF-I).
引用
收藏
页码:622 / 630
页数:9
相关论文
共 40 条
[1]   TISSUE DISTRIBUTION AND REGULATION OF INSULIN-LIKE GROWTH-FACTOR (IGF)-BINDING PROTEIN-3 MESSENGER-RIBONUCLEIC-ACID (MESSENGER-RNA) IN THE RAT - COMPARISON WITH IGF-I MESSENGER-RNA EXPRESSION [J].
ALBISTON, AL ;
HERINGTON, AC .
ENDOCRINOLOGY, 1992, 130 (01) :497-502
[2]   DIFFERENTIAL CELLULAR SYNTHESIS OF INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-1 (IGFBP-1) AND IGFBP-3 WITHIN HUMAN LIVER [J].
ARANY, E ;
AFFORD, S ;
STRAIN, AJ ;
WINWOOD, PJ ;
ARTHUR, MJP ;
HILL, DJ .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1994, 79 (06) :1871-1876
[3]   THE EFFECTS OF SUBCUTANEOUS INSULIN-LIKE GROWTH-FACTOR-I INFUSION IN INSULIN-DEPENDENT DIABETES-MELLITUS [J].
BACH, MA ;
CHIN, E ;
BONDY, CA .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1994, 79 (04) :1040-1045
[5]   STRUCTURE OF THE MR 140,000 GROWTH HORMONE-DEPENDENT INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEIN COMPLEX - DETERMINATION BY RECONSTITUTION AND AFFINITY-LABELING [J].
BAXTER, RC ;
MARTIN, JL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (18) :6898-6902
[6]   AN L-ARGININE-DEPENDENT MECHANISM MEDIATES KUPFFER CELL-INHIBITION OF HEPATOCYTE PROTEIN-SYNTHESIS INVITRO [J].
BILLIAR, TR ;
CURRAN, RD ;
STUEHR, DJ ;
WEST, MA ;
BENTZ, BG ;
SIMMONS, RL .
JOURNAL OF EXPERIMENTAL MEDICINE, 1989, 169 (04) :1467-1472
[7]  
BILLIAR TR, 1989, ARCH SURG-CHICAGO, V124, P1416
[8]   INSULIN-LIKE GROWTH FACTOR-I (IGF-I)-BINDING PROTEIN COMPLEX IS A BETTER MITOGEN THAN FREE IGF-I [J].
BLUM, WF ;
JENNE, EW ;
REPPIN, F ;
KIETZMANN, K ;
RANKE, MB ;
BIERICH, JR .
ENDOCRINOLOGY, 1989, 125 (02) :766-772
[9]   CHARACTERIZATION OF THE INCREASED BIOLOGICAL POTENCY IN BALB/C 3T3 CELLS OF 2 ANALOGS OF HUMAN INSULINLIKE GROWTH FACTOR-I WHICH HAVE REDUCED AFFINITY FOR THE 28-K CELL-DERIVED BINDING-PROTEIN [J].
CASCIERI, MA ;
HAYES, NS ;
BAYNE, ML .
JOURNAL OF CELLULAR PHYSIOLOGY, 1989, 139 (01) :181-188
[10]   ANALYSIS OF THE INTERACTION OF INSULIN-LIKE GROWTH-FACTOR-I (IGF-I) ANALOGS WITH THE IGF-I RECEPTOR AND IGF-BINDING PROTEINS [J].
CASCIERI, MA ;
BAYNE, ML .
HORMONE RESEARCH, 1994, 41 :80-86