Insulin-Like Growth Factor (IGF) and IGF-Binding Proteins: Comparison of Human Serum and Lymph*

Abstract

The extent to which the association between insulin-like growth factors (IGFs) and their specific binding proteins (BPs) prevents their crossing the capillary barrier was studied by comparing their distribution in serum with that in samples of lymph collected from the lower leg of five subjects undergoing radiographical investigation of the lymphatic system. The IGF concentrations in lymph were 10-30% of the corresponding serum levels, and in each subject the ratios of IGF-I and IGF-II in the lymph to those in the serum were similar. Western blot analysis of the BPs revealed that the five molecular forms identified in serum also were present in lymph, but in significantly smaller quantities. The 41.5K and 38.5K forms, which constitute the binding units of the large complex (approximately 150K) of serum and are also capable of binding IGFs in monomeric form, were present in smaller amounts than the 34K, 30K and 24K forms, which belong specifically to the small complex (approximately 40K) of serum. The BPs extracted from lymph were similar to those of the small complex, with a preferential affinity for IGF-II and only half of the affinity for IGF-I of the BPs extracted from serum. With neutral pH gel filtration of lymph, more than 90% of IGFs and binding activity eluted with the material in the area of the 40K zone. These data indicate that the 150K IGF-BP complexes do not cross the capillary barrier, whereas the 40K complexes do. The function of the former may be to provide a reservoir and buffering action of the IGFs, whereas the latter may be involved in the transport of the IGFs to their target cells.

Can "big" insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia?

“…However, this is not yet sufficient to explain hypoglycemia in tumor patients: in normal serum > 98% of total IGF II is bound to IGFBPs (30), and 70-80% is associated with a 1 50-kD IGFBP complex (31 ). The bioavailability ofthis latter IGF pool is largely restricted by the capillary barrier (31,32 The distribution ofbig IGF II between the 150-and 50-kD IGFBP complexes and its bioavailability. Besides the IGF pool associated with the 1 50-kD complex, two other IGF pools exist in serum; 20-30% ofthe total IGF ofnormal serum resides in a 50-kD IGFBP complex (31 ).…”

“…The 50-kD binding protein complex of normal serum contains mainly IGFBP-2 and relatively little IGFBP-3 (12,33). This complex can cross the capillary barrier (32) and may thus render its IGF bioavailable to tissues. A third IGF pool consists of free IGF in equilibrium with the two IGFBP complexes.…”

Insulin-like growth factor-binding protein 5 ( Igfbp5 ) compromises survival, growth, muscle development, and fertility in mice

“…The proportion of different IGFBPs in serum is also important, and, in this regard, IGFBP-5 can effectively compete with IGFBP-3 for serum ternary complex formation with the acid-labile subunit in vivo (38). The demonstration of IGFBP-5-myc protein at an appropriate M r for ternary complex formation suggests that IGFBP-5 could have displaced IGFBP-3 from this complex, retaining circulating IGF in a relatively tightly bound ternary complex (39). Because noncomplexed IGFBP-3 is susceptible to proteolysis (40), the decrease in circulating IGFBP-3 concentrations was consistent with degradation of displaced IGFBP-3.…”

Maternal serum insulin-like growth factor-binding protein-3 (IGFBP-3) at 11–13 weeks in preeclampsia

“…16,17 In the circulation, IGFBP-3 binds to approximately 95% of IGF-I and IGF-II and this complex prolongs the half-life of IGFs and protects them from degradation. [16][17][18][19] An endogenous pregnancy-related IGFBP-3 proteolytic activity is considered a fundamental mechanism to increase the bioavailability of IGF-I, [20][21][22] which is a mitogenic polypeptide that stimulates cellular proliferation and differentiation and is involved in the regulation of trophoblast invasion and placental development. [23][24][25] In addition, IGFBP-3 can inhibit cell proliferation and stimulate apoptosis via non-IGFdependent pathways.…”