Endocrine Abstracts (2008) 16 OC1.7

Intermittent high glucose concentrations reduce neuronal precursor proliferation by altering the IGF system: the involvement of the neuroprotective factor seladin-1

Stefano Giannini1, Anna Pezzatini1, Paola Luciani2, Cinzia Manuelli3, Susanna Benvenuti2, Ilaria Cellai2, Cristiana Deledda2, Gabriella Barbara Vannelli4, Carlo Maria Rotella1, Mario Serio2 & Alessandro Peri2

1Diabetes and Metabolic Diseases Unit, University of Florence, Florence, Italy; 2Endocrine Unit, University of Florence, Florence, Italy; 3Institute of Dermatology and Venerology, University of Florence, Florence, Italy; 4Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy.

The exposure of cells to high glucose concentrations is considered a determinant of diabetic neuropathy. Conversely, members of the Insulin-like Growth Factor (IGF) system are well known neurotrophic factors. Here, we investigated the effects of constant and intermittent high glucose concentrations on IGF-I and IGF Binding Proteins (IGFBPs) in human neuroblast long-term cell cultures (FNC). We first demonstrated that FNC express the IGF-I receptor, and express and release in the culture medium IGF-I, IGFBP-2 and IGFBP-4. IGF-I secretion was significantly increased by the exposure to 17β-estradiol (10 nM), in agreement with the reported cross-talk between the IGF system and estrogen in neuronal cells. FNC treatment with IGF-I (100 nM) increased the release of IGFBP-2, that is known to facilitate the binding of IGF-I to its receptor, whereas it reduced the release of IGFBP-4, that is considered an inhibitor of the biological actions of IGF-I. In addition, IGF-I stimulated FNC cell proliferation in a dose-dependent manner (1–100 nM). Previous data showed that 17β-estradiol increases the expression of the Alzheimer’ disease related gene seladin-1, which acts as a pro-survival factor for neuronal cells. Similarly, here we observed that also IGF-I (10 nM) significantly increased the expression of this gene. In contrast with the effects of IGF-I, the exposure to intermittent (20/10 mM), but not stable (20 mM), high glucose concentrations inhibited FNC growth, and determined a decreased release of IGF-I and IGF-BP2. In addition, high glucose decreased the expression of seladin-1. In conclusion, our results suggest for the first time that intermittent high glucose concentrations, similar to those observed in poorly controlled diabetic patients, may contribute to the development of diabetic neuropathy by interfering with the trophic effects exerted by the IGF system, which might be mediated, at least partially, by the pro-survival factor seladin-1.