The ALR2 gene is localized on chromosome 7q35 (AKR1B1, NM001628) (45). Pseudogenes have also been found on other chromosomes (46). The gene extends more than 18 kb and contains 10 exons that code for a 1384 bp mRNA. The basal promoter activity is located between position -192 and +31. Several ds-regulatory elements have been isolated and point mutations in certain sequences such as the TATTTA reduced promoter activity to 35% of the wild-type DNA. The basal promoter region contains a consensus sequence for an androgen response element, three osmotic response element (ORE) sequences, ORE-A, ORE-B, and ORE-C, a sequence homologous to an Ap-1 site and also a microsatellite dinucleotide (AC) repeat sequence. In man, the ORE sequences are situated approximately 1200 bp upstream of the initiation site and maximum activity is obtained when all three ORE sequences are present (47). The tonicity-binding protein (TonEBP), has recently been characterized and shown to bind to the ORE sequences and now known to be nuclear factor of activated T-cells-5 (48,49). TonEBP is a homodimer that adopts a NF-KB-like structure to allow it to bind to DNA and completely encircle the helix to increase the kinetic stability of the TonEBP-DNA complex. High glucose increases nuclear factor of activated T-cells-5 binding to the OREs, which are located in the promoter region of the gene. This was significantly increased in patients with diabetic microvascular complications in comparison with those without.

AKR1B1 can be activated by a number of factors. For instance, tumor necrosis factor can initiate its expression possibly by the binding of the transcription factor NF-kB to the NF-kB regulatory element that shares extensive homology with the ORE (49).

Table 2

Candidate Gene Studies in Diabetic Neuropathy

Table 2

Candidate Gene Studies in Diabetic Neuropathy






SOD2 and SOD3




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