ABSTRACT
Galactosemic animal models have become important tools for understanding complications of diabetes at the cellular level where some of the earliest changes occur, especially as applied to diabetic ocular complications (Engerman and Kern, 1984; 1995a; Kador et al., 1988; 1990; 1994; 1995; Robison et al., 1983; 1989; 1990a; 1995a; 1995b; Takahashi et al., 1992). It seems incredible that a normal animal fed a diet containing 30% to 64% galactose would develop ocular complications that mimic closely those of diabetes. Yet this is what the evidence indicates, probably because the primary underlying mechanisms causing galactosemic and diabetic complications are the same or very similar (Robison et al., 1995a). Even more surprising, the diabetic-like complications occur sooner and are more severe in galactosemic than in diabetic animals. Although other possibilities will be discussed, the most probable explanation comes from the fact that galactosemia, like hyperglycemia, results in increased flux through aldose reductase, the first enzyme of the polyol pathway, resulting in the accumulation of polyol in all tissues that do not require insulin for hexose uptake (Figure 1). Eventually, all tissues that accumulate polyol (galactitol or sorbitol, respectively) develop ocular complications characteristic of diabetes (Dvornik, 1987; Robison, 1995a). The mimicking of diabetic retinal microangiopathies is extraordinary (Robison et al., 1995a). The spectrum of microangiopathies characteristic of human diabetic retinopathy is very specific, not being completely matched by any other ocular condition in humans (Table 1). Yet galactosemic animals develop, in the same sequence, the entire spectrum of lesions otherwise unique to diabetic retinopathy. The fact that increased tissue polyol accumulation is common to both galactosemic rat and diabetic human retinas implicates flux through aldose reductase. Confirmation of the key role of aldose reductase has come from several studies on diabetic rats (Kojima et al., 1985a; 1985b; Chakrabarti and Sima, 1987; 1989), on galactosemic rats
(Robison et al., 1983; 1989; 1990a; 1990b; 1995b; 1996; Frank et al., 1997), and on galactosemic dogs (Akagi and Kador, 1990; Kador et al., 1994). In these studies various structurally distinct, specific inhibitors of aldose reductase ameliorated or prevented diabetic-like retinopathy and other ocular complications. The demonstration that aldose reductase has a fourfold greater affinity for galactose than for glucose (Sato and Kador, 1990) provides an explanation for the acceleration of diabetic-like ocular complications observed in galactosemic animals.
