Insulin and insulin-like growth factors (IGFs) stimulate production of IGF-binding proteins by ovarian granulosa cells

Abstract

Ligand blot analysis of granulosa cell (GC)-conditioned culture medium revealed several easily measurable insulin-like growth factor (IGF)-binding proteins (IGFBPs), including IGFBP-3 [40-44 kilodaltons (kDa)] and IGFBP-2 (34 kDa). In the present study, IGF-I, in a dose-dependent manner, significantly stimulated the production of these IGFBPs. Insulin, but not IGF-II, mimicked IGF-I's action on IGFBP-3 and -2 production, but was less potent. The synthetic IGF, long R3-IGF-I, which has very low affinity for IGFBPs and only slightly reduced affinity for the IGF-I (type I) receptor, had significantly greater potency in stimulating IGFBP-3 and -2 production compared to IGF-I. Des-(1-3)-IGF-I had similar effects. IGF-I, IGF-II, and the IGF-I analogs, but not insulin, also induced production of an unidentified 30-kDa IGFBP not normally detectable in these cultures. However, in the presence of epidermal growth factor (which was without independent effect on the 30-kDa IGFBP), insulin also induced this 30-kDa IGFBP. By Northern analysis the expression of IGFBP-3 mRNA was found to be significantly stimulated by IGF-I. In summary, insulin stimulated IGFBP-3 and -2 production in a manner that mimics that of IGF-I and the more potent long R3-IGF-I. However, its low potency suggested that IGFBP production is regulated via the IGF-I (type I) receptor. The much higher potency of long R3-IGF-I compared to that of IGF-I suggests that the IGFBPs themselves modulate the action of IGFs by sequestering exogenous IGFs. Thus, one cellular response to IGF stimulation is the production of IGFBPs, which, in turn, reduce or negate the biological activity of the IGFs. The effects of insulin-like peptides are exerted at least in part by increasing levels of mRNA for specific BPs.

Leptin Directly Controls Secretory Activity of Human Ovarian Granulosa Cells: Possible Inter-Relationship with the IGF/IGFBP System

“…The inhibitory influence of antiserum on IGFBP-3 level observed in our experiments do not correspond to the report of Grimes and Hammond [21] on stimulatory effect of IGF-I on IGFBP-3 production by cultured ovine granulosa cells. This discrepancy could be due to different experimental conditions (species, culture) or the secondary effect of IGF-I.…”

GATA Depletion Impacts Insulin-like Growth Factor 1 mRNA and Protein Levels in Luteinizing Porcine Granulosa Cells1

“…In previous reports, IGF1 did not increase IGFBP4 mRNA, although follicle-stimulating hormone (FSH) did in primary granulosa cells [43,44]. IGF1 either stimulated or had no effect on IGFBP3 mRNA levels in granulosa cells [44,49] and was regulated by FSH in a biphasic manner [50]. Despite the findings that some IGFBP mRNAs were altered by specific GATA RNAi conditions, IGFBP binding of [ 125 I]IGF1 in Western ligand blots was not altered by GATA reduction, indicating that RNAi conditions did not affect steady-state IGFBP levels.…”

Effect of Somatotropin and/or Equine Chorionic Gonadotropin on Serum and Follicular Insulin-Like Growth Factor I and Insulin-Like Growth Factor Binding Proteins in Cattle1

“…Addition of exogenous IGFBP has been shown to inhibit the ability of FSH and IGF-I to stimulate steroidogenesis, cAMP generation, and DNA synthesis in cultured granulosa cells [12,79,80]. Recently, IGF analogues with reduced affinities for IGFBP but not the Type-I receptor were shown to be more effective than IGF-I in enhancing FSHstimulated accumulation of P 4 by rat granulosa cells [81] and in stimulating IGFBP synthesis [82]. Since FSH also has been shown'to inhibit the secretion of IGFBP by granulosa cells [61,62,77], this may represent a mechanism by which IGF availability is increased to promote granulosa cell growth.…”

“…Since FSH also has been shown'to inhibit the secretion of IGFBP by granulosa cells [61,62,77], this may represent a mechanism by which IGF availability is increased to promote granulosa cell growth. Furthermore, activation of Type-I IGF receptors in porcine granulosa cells by IGF-I results in increased synthesis and release of IGFBP, which, in turn, appear to sequester and neutralize IGF-I [82]. However, several forms of IGFBP have also been shown to stimulate IGF bioactivity in other cell types under certain conditions [83].…”