Postoperative induction of insulin-like growth factor binding protein-3 proteolytic activity: relation to insulin and insulin sensitivity.
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 colo-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.
Bang
P
P
Department of Woman and Child Health, Karolinska Institute and Hospital, Stockholm, Sweden. peter.bang@kbh.ki.se
Nygren
J
J
Carlsson-Skwirut
C
C
Thorell
A
A
Ljungqvist
O
O
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D015153:Blotting, Western; D010450:Endopeptidases / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D005947:Glucose / Q000493:pharmacokinetics / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis*; D008875:Middle Aged; D011184:Postoperative Period
D007004:Hypoglycemic Agents; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D010450:Endopeptidases; D005947:Glucose