Glucose inhibition of human fibroblast proliferation and response to growth factors is prevented by inhibitors of aldose reductase

Mechanisms of Ageing and Development
W L SibbittD L Vander Jagt

Abstract

Diabetes mellitus is associated with premature senescence of cultured dermal fibroblasts. The present study investigated the effect of elevated glucose concentrations on cultured human fibroblasts from normal donors. Mean population doubling times, population doublings until senescence, saturation density at confluence (cells/cm2), tritiated thymidine incorporation, and response to platelet-derived growth factor (PDGF) were inhibited with the increasing glucose concentrations (11.0, 22, 44, or 55 mM glucose) (P less than 0.05). Replicative life span was markedly diminished by multiple passages in high glucose medium (5.5 mM glucose: 62.4 +/- 7.9 population doublings; 22 mM glucose: 22.8 +/- 3.4 population doublings: P less than 0.05). Aldose reductase activity was present in the cultured fibroblasts (3.9 +/- 0.5 nmol/min per mg protein), and inhibitors of aldose reductase, including sorbinil (10(-4) M--10(-6) M) and tolrestat (10(-6) M--10(-8) M), completely prevented glucose-mediated inhibition of fibroblast proliferation, restored the response to PDGF, and allowed a normal replicative life span. Myo-inositol (11 microM--5.5 mM) also reversed the adverse effects of glucose. These in vitro data demonstrate that elevated concent...Continue Reading

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Citations

Jan 1, 1992·Pharmacology & Therapeutics·D R TomlinsonA L Carrington
Jan 1, 1991·Experimental Gerontology·H R Hirsch, M Witten
Jan 27, 1998·Journal of Diabetes and Its Complications·R P EatonJ M Bicknell
Oct 24, 2000·Kidney International·A ShostakL Gotloib
Apr 19, 2006·International Wound Journal·Hiroto TerashiCynthia L Marcelo
Jun 1, 1997·Glia·C Jacquin-Becker, G Labourdette
Jul 31, 2002·Biochemical and Biophysical Research Communications·Shraga BlazerKarl L Skorecki

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