Effects of long-acting somatostatin analogues on redox systems in rat lens in experimental diabetes

Cataract formation is a major cause of blindness in ageing and in diabetes mellitus (see Resnikoff et al. 2004). Extensive studies have been made of the early biochemical changes involved in cataract formation using as model lenses from streptozotocin or alloxan diabetic rats, many of these centring upon early changes in the metabolite profile. Changes in the integration of pathways linked to glucose metabolism, redox systems resulting from hyperglycaemia, the role of the NADPH-dependent aldo-keto reductase, the rate-limiting enzyme of the polyol pathway, and the inhibition of this enzyme by Sorbinil have been discussed (Gabbay 1973; Kinoshita et al. 1979; Varma 1980; Gonzalez et al.1983, 1986; McLean et al. 1985; Brownlee 2005; Lu 2009). In parallel, measures to correct the redox state changes by the use of compounds such as pyruvate and ascorbate have been studied (Zhao et al. 2000; Hedge & Varma 2004). Glutathione was a focal point of the present study, because as reviewed by Lu (2009), glutathione has diverse functions including antioxidant defence, maintenance of thiol groups and cell proliferation. Alterations in the regulation of glutathione synthesis in ageing and disease, including diabetes and insulin treatment, have been reviewed by Lu (2009) with emphasis on the regulation of the rate-limiting enzyme glutamate cysteine ligase and the coordinated change in glutathione synthase. At present, there does not appear to be information on changes in these enzymes in the rat lens in diabetes although the decrease in lens glutathione is well established. Recently, attention has been drawn to the role of growth factors such as fibroblast growth factors and insulin-like growth factor 1 and to the effect of a somatostatin analogue, octreotide, on lens epithelial cell proliferation (Baldysiak-Figiel et al. 2005; Kampmeier et al. 2006). IGF-1 has been shown to regulate lens cell differentiation and proliferation and specifically binds to bovine lens epithelial cells (Palmade et al. 1994; Klok et al. 1998). It has also been shown that insulin and IGF-1 affect the protein composition of the lens fibre cells with possible consequences for cataract formation (Civil et al. 2000). In this context, it is significant that high levels of IGF 1 were found in the vitreous in diabetic patients (Boehm et al. 2001) and that Octreotide has been shown to have anti-proliferative effects on endothelial cells and to reduce the progression of diabetic retinopathy (Boehm et al. 2001; Boehm 2007). Thus, the use of somatostatin receptor ligands has been proposed for use in obesity and diabetic complications including cataract formation and retinopathy (Civil et al. 2000; Boehm & Lustig 2002; Cervia et al. 2008). The present study measures the effects of somatostatin analogues on early changes in glutathione, NADPH and ATP content of the rat lens in experimental diabetes, metabolites central to the maintenance of normal lens structure and function.