A number of genetic models have been proposed for the interaction of the diabetic milieu with genetic background of the individual. These include models in which the genetic factors modify the progression of the disease or possibly glycemic control (18,19). Clearly, this would explain why some patients with well-controlled diabetes still develop complications, wheras others with poorly controlled diabetes "escape" any complications. There is a wide-spectrum in the incidence of microvascular disease between patients. For example, it is well-known that the majority of patients with nephropathy have retinopathy, but there are those who have retinopathy and normal renal function even after many years of diabetes. This heterogeneity in phenotype is a major problem in the design and interpretation of genetic studies. Until the genetic factors that contribute to each phenotype are known, it is unwise to assume that the same genes contribute to the same degree in all the tissues.
Previous family, transracial, and epidemiological studies strongly suggest that genetic factors are important in the susceptibility to diabetic nephropathy as well as retinopathy. These findings were supported by the DCCT showing familial clustering of diabetic microvascular complications (20). The sequencing of the human genome now enables the positional cloning of multifactorial disease genes to be pursued. Several types of mutations exist including single nucleotide polymorphisms (SNPs), dinucleotide repeats, and microsatellites. These polymorphisms might be located in the promoter region of the gene and affect transcription or translation, and not infrequently determine the level of expression of the protein product (21). High density SNP maps have been used to identify the potential genetic components of complex disease (22). To date, there are only limited studies of whole genome screening for determinants of microvascular disease. Sib-pair linkage analysis was used to identify susceptibility loci for diabetic nephropa-thy in Pima Indians with T2DM (23). The study suggested that chromosomes 3 and 9 might be important areas, but the strongest linkage was with the region harbouring ALR2 on chromosome 7. Recently, chromosomes 10 has been identified as a possible region for determining the decline of renal function, whereas chromosome 18 has been postulated to be important in caucasoid T2DM patients (24-26). Tanaka et al. (27) have reported association of solute-carrier family of 12 members, three with diabetic nephropathy, in a Japanese study by using the genome-wide analysis.
Genetic models can also be used to identify the susceptibility risk factor. Rogus et al. (28) have studied the genetic association between diabetic complications and diabetes duration by using a genetic model. Genetic models might be used to study a single major genetic effect whereby, carriage/noncarriage of a risk allele essentially indicates who will become affected, and a subtle minor genetic effect that simply shortens or lengthens the duration at which onset occurs. On a broader level, these results highlight the need to be cognizant of diabetes duration before onset of proteinuria or other late diabetic complications in family-based trio studies. To date, there have been no family studies looking at diabetic neuropathy.
The understanding of the mechanisms of brain and nervous system function has been greatly aided by the discovery of genes responsible for specific neurological disorders. These results will hopefully allow the genetic factors responsible for diabetic neuropathy to be identified and enable the following objectives to be realized:
1. Identification of the culprit gene(s) and the associated defect;
2. Understanding the mechanism by which the gene is regulated in the normal and diabetic state;
3. Developing molecular diagnostic approaches; and
4. Applications of this knowledge toward development of therapeutic regimens.
Any gene, that is involved in the aforementioned pathways could become a candidate gene. In the next sections the evidence for putative candidate genes will be reviewed (Tables 1-3).
Aldose Reductase (ALR2 or AKR1B1)
Under normal conditions glucose is metabolized by three key pathways, primarily by a hexokinase-dependent phosphorylating pathway to form glucose 6-phosphate, which then enters the glycolytic pathway to form lactate, or the hexose monophosphate shunt to form pentose-phosphate. Second, glucose might be oxidized to gluconic acid through an NAD+-dependent glucose dehydrogenase. Finally, nonphosphorylated glucose might enter an accessory pathway of glucose metabolism known as the polyol pathway. Aldose reductase is the first and rate-limiting enzyme in the polyol pathway. It is widely distributed in human tissues including Schwann cells. Reduced glutathione synthesis, impaired nitric oxide synthesis, reduced Na+, K+-ATPase activity, increased protein kinase (PK)-C activity as well as a redox imbalance have all been identified as critical changes secondary to enhanced aldose reductase activity that precipitate the development of diabetic neuropathy (29-34). Aldose reductase inhibitors can prevent excess polyol pathway flux, and hence these agents might prevent nerve conduction velocity deficits by preventing p38 MAP kinase activation (35). The overexpression of human aldose reductase in mice with diabetes is associated with neuropathy and can be prevented by an aldose reductase inhibitor (36). Transgenic mice overexpressing aldose reductase in Schwann cells show more severe nerve conduction velocity deficit and oxidative stress under hyperglycemic stress (37). In those mice, the level of reduced glu-tathione (antioxidant) in the sciatic nerve was found to be correlated with the severity of motor nerve conduction velocity deficit. Growing evidence indicates that ALR2 has a key role in oxidative stress in the peripheral nerve and contributes to superoxide production by the vascular endothelium (review in ref. 38).
ALR2 is a member of the NADPH-dependent monomeric aldo-keto oxidoreductases with a wide array of substrates. ALR2 can reduce the byproducts of glucose metabolism, such as methyglyoxal, 4-hydroxynonenal, and 3-deoxyglucosone (39,40). Glucose is not the preferred substrate for ALR2. It is more efficient in reducing various aromatic and aliphatic aldehydes such as glyceraldehyde (41).
ALR2 has been isolated from a number of tissues in man (42-45). It is possible that the high levels of ALR2 enzyme activity and protein are genetically determined because of polymorphisms either in the coding or, promoter region of the gene. These genetic variations might in turn modulate the risk of diabetic microvascular complications in association with various other metabolic, genetic, and environmental factors.
Summary of Studies Investigating Polymorphisms Within the Promoter Region of the Aldose Reductase Gene in T1DM and T2DM
Microvascular Polymorphisms Ethnic population complication studied Association References
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