Postoperative induction of insulin-like growth factor binding protein-3 proteolytic activity: Relation to insulin and insulin sensitivity

被引:48
作者
Bang, P [1 ]
Nygren, J
Carlsson-Skwirut, C
Thorell, A
Ljungqvist, O
机构
[1] Karolinska Inst, Karolinska Hosp, Dept Woman & Child Hlth, Pediat Endocrinol Unit, S-17176 Stockholm, Sweden
[2] Karolinska Hosp & Inst, Dept Surg, S-17176 Stockholm, Sweden
关键词
D O I
10.1210/jc.83.7.2509
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Increased serum insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) proteolytic activity (IGFBP-3-PA) has been demonstrated in a number of clinical states of insulin resistance, including severe illness, after surgery, and in noninsulin-dependent diabetes mellitus. In the present study we assessed the role of insulin sensitivity in expression of IGFBP-3-PA in serum. In 18 patients studied, a significant increase in IGFBP-3-PA (P < 0.005) was demonstrated after cole-rectal surgery. Eight patients receiving an oral glucose load before surgery demonstrated a significant greater relative increase in IGFBP-3-PA compared with 10 patients not receiving glucose (32.9 +/- 7.1% vs. 8.6 +/- 6.7%, respectively; P < 0.05). Both groups had reduced insulin sensitivity after surgery(-58 +/- 4%; P < 0.0001; n = 18), as determined by hyperinsulinemic, normoglycemic clamps; however, the group not receiving glucose displayed 18% less insulin sensitivity than the oral glucose load group (P < 0.05). Multiple regression analysis demonstrated that the relative changes in IGFBP-3-PA and C peptide levels were inversely correlated (P < 0.05), suggesting that increased IGFBP-3-PA, presumably increasing IGF bioavailability, may be associated with decreased insulin demands. Interestingly, insulin infusion during the 4-h hyperinsulinemic, normoglycemic clamp performed 24 h after surgery (post-op) resulted in a further increase in IGFBP-3-PA in both groups (P < 0.005), whereas no significant responses could be demonstrated during the pre-op clamp. The expression of increased IGFBP-3-PA was accompanied by conversion of endogenous intact 39/42-kDa IGFBP-3 into its 30-kDa fragmented form as determined by Western immunoblotting, and this conversion was virtually complete after the 4-h post-op clamp in patients displaying marked increases in IGFBP-3-PA. Characterization of the IGFBP-3-PA demonstrated that it was specific for IGFBP-3, as no degradation of IGFBP-1 and -2 was detected, and the use of various protease inhibitors demonstrated that serine proteases and possibly matrix metalloproteinases contribute to the increased IGFBP-3-PA level after surgery. We propose that IGF bioavailability may be increased by the induction of IGFBP-3-PA in insulin-resistant subjects, and that insulin regulates IGFBP-3-PA in this state.
引用
收藏
页码:2509 / 2515
页数:7
相关论文
共 37 条
[1]   AUTOCRINE REGULATION OF CELL-PROLIFERATION BY THE INSULIN-LIKE GROWTH-FACTOR (IGF) AND IGF BINDING PROTEIN-3 PROTEASE SYSTEM IN A HUMAN PROSTATE CARCINOMA CELL-LINE (PC-3) [J].
ANGELLOZNICOUD, P ;
BINOUX, M .
ENDOCRINOLOGY, 1995, 136 (12) :5485-5492
[2]   Human pregnancy serum contains at least two distinct proteolytic activities with the ability to degrade insulin-like growth factor finding protein-3 [J].
Bang, P ;
Fielder, PJ .
ENDOCRINOLOGY, 1997, 138 (09) :3912-3917
[3]   INCREASED PROTEOLYSIS OF INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-3 (IGFBP-3) IN NONINSULIN-DEPENDENT DIABETES-MELLITUS SERUM, WITH ELEVATION OF A 29-KILODALTON (KDA) GLYCOSYLATED IGFBP-3 FRAGMENT CONTAINED IN THE APPROXIMATELY 130-KDA TO 150-KDA TERNARY COMPLEX [J].
BANG, P ;
BRISMAR, K ;
ROSENFELD, RG .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1994, 78 (05) :1119-1127
[4]  
BANG P, 1994, THESIS KAROLINSKA I
[5]  
Bang Peter, 1995, Progress in Growth Factor Research, V6, P285, DOI 10.1016/0955-2235(96)00007-5
[6]   TISSUE LOCALIZATION OF PERFUSED ENDOTHELIAL-CELL IGF BINDING-PROTEIN IS MARKEDLY ALTERED BY ASSOCIATION WITH IGF-I [J].
BAR, RS ;
BOES, M ;
DAKE, BL ;
SANDRA, A ;
BAYNE, M ;
CASCIERI, M ;
BOOTH, BA .
ENDOCRINOLOGY, 1990, 127 (06) :3243-3245
[7]  
BAXTER RC, 1989, J BIOL CHEM, V264, P11843
[8]  
BINOUX M, 1994, CURRENT DIRECTIONS I, P293
[9]  
BLAT C, 1994, J CLIN INVEST, V93, P2226
[10]  
Conover Cheryl A., 1995, Progress in Growth Factor Research, V6, P301, DOI 10.1016/0955-2235(95)00032-1