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Aldose Reductase Gene Polymorphisms and Peripheral Nerve Function in Patients With Type 2 Diabetes

¹ Department of Clinical Nutrition, University of Kuopio, Kuopio, Finland
² Department of Medicine, University of Kuopio, Kuopio, Finland
³ Department of Clinical Neurophysiology, University of Kuopio, Kuopio, Finland

Address correspondence and reprint requests to Katariina Sivenius, MD, Department of Clinical Nutrition, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: ksiveniu{at}hytti.uku.fi

	ABSTRACT

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OBJECTIVE—We screened the human aldose reductase (ALR) gene for DNA sequence variants in type 2 diabetic and nondiabetic subjects and investigated whether the previously reported and novel polymorphisms were associated with neurophysiologic deterioration and clinical peripheral neuropathy.

RESEARCH DESIGN AND METHODS—The study population included 85 Finnish type 2 diabetic and 126 nondiabetic subjects. The genetic analyses were performed using the PCR, single-strand conformation polymorphism, restriction fragment-length polymorphism, and automated laser fluorescence scanning analyses. A detailed neurologic examination and neurophysiologic analyses were performed at the time of diagnosis and at the 10-year examination.

RESULTS—The genetic screening identified four polymorphisms: C-106T, C-11G, A11370G, and C19739A. The C and Z-2 alleles of the C-106T polymorphism and the previously reported (CA)_n repeat marker were more frequent in type 2 diabetic subjects than in nondiabetic subjects. At baseline, the diabetic subjects with the T allele of the C-106T polymorphism had lower sensory response amplitude values in the peroneal (P = 0.025), sural (P = 0.007), and radial (P = 0.057) nerves and, during follow-up, a greater decrease in the conduction velocity of the motor peroneal nerve than those with the C-106C genotype. No associations were found between the polymorphisms examined and clinical polyneuropathy.

CONCLUSIONS—The C-106T polymorphism of the ALR gene may contribute to an early development of neurophysiologic deterioration in type 2 diabetic patients.

Abbreviations: ALR, aldose reductase • NCV, nerve conduction velocity • RA, response amplitude • RFLP, restriction fragment-length polymorphism • SSCP, single-strand conformation polymorphism

	INTRODUCTION

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Chronic hyperglycemia is a well-established cause of microvascular complications (1,2), but genetic factors may lie behind individual susceptibility. Aldose reductase (ALR)2 is the first and rate-limiting enzyme of the polyol pathway that catalyzes NADPH-dependent reduction of glucose to sorbitol. ALR2 is expressed in many tissues in humans and may participate in the pathogenesis of diabetic microvascular complications (3). The functional ALR2 gene consists of 10 exons, and it is located on chromosome 7q35 (4). The promoter area of the gene has also been characterized (5). Recently, a (CA)_n dinucleotide repeat polymorphism 2.1 kb upstream of the transcription start site of ALR2 was identified (6), but its associations with microvascular complications have been controversial. The Z-2 allele of the (CA)_n repeat marker (Z being the "basic" allele of the marker and having 24 CA dinucleotide repeats) has been associated with diabetic neuropathy (7) but not consistently (8,9). An increase in ALR2 mRNA in Z-2 allele carriers among patients with diabetic nephropathy has also been found (10). More recently, a polymorphism at position –106 in the promoter area of the ALR2 gene (C-106T) was described and has been associated with retinopathy (11,12) and nephropathy (13,14) in type 1 and type 2 diabetic patients. The Z-2 allele has been in linkage disequilibrium with both the C (11,12) and T (13,14) alleles of the C-106T polymorphism.

The purpose of the present study was to screen the 10 exons and the promoter region of the ALR2 gene for DNA sequence variants in a population of middle-aged newly diagnosed type 2 diabetic patients and nondiabetic control subjects from eastern Finland. We also investigated the associations of the previously reported and novel polymorphisms with neurophysiologic deterioration and frequency of clinical peripheral neuropathy in diabetic subjects.

	RESEARCH DESIGN AND METHODS

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The original study population consisted of 133 newly diagnosed patients with type 2 diabetes (70 men and 63 women) and 144 nondiabetic control subjects (62 men and 82 women) aged 45–64 years at baseline examination in 1979–1981. The patients were reexamined after 10 years. The formation and representativeness of the study populations have been described earlier (15,16). The diagnosis of diabetes was made in the clinical setting, and it was confirmed by an oral glucose tolerance test (17). The nondiabetic control subjects were randomly selected from the population register of the study area. Approval for the study was given by the ethics committee of the Kuopio University and Kuopio University Hospital, and informed consent was obtained.

At baseline, all diabetic patients were treated with diet only. The frequency of drug treatment increased with time: at the 10-year examination, 16 (18.8%) diabetic subjects were treated with diet only, 49 (57.6%) were treated with oral hypoglycemic drugs, and 20 (23.5%) were treated with insulin.

During the 10-year follow-up, 36 diabetic patients and 8 control subjects died. In addition, DNA samples were not available from all original study subjects, and therefore, the screening for the polymorphisms of the ALR2 gene was performed in 85 type 2 diabetic patients and 126 nondiabetic control subjects. The subjects who died during the follow-up did not have more neurophysiologic abnormalities earlier than those who survived (18).

Clinical and biochemical characteristics
At baseline, the following examinations were performed: clinical history, anthropometric characteristics (BMI), oral glucose tolerance test, and plasma insulin. At the 10-year examination, the measurements were repeated, and in addition, HbA_1c was assessed. The exclusion criteria for the study subjects, as well as the methods, have been previously reported (15,16). The basic characteristics are presented in Table 1.

Neurologic examination and definition of diabetic polyneuropathy
A detailed clinical neurologic examination including a standardized questionnaire about neuropathic symptoms was performed at baseline and at 10 years (18). The criteria for diabetic polyneuropathy used in the present study were the same as previously described (18).

Determination of the polymorphisms in the ALR2 gene
The ALR2 gene was screened for DNA sequence polymorphisms by performing the PCR and single-strand conformation polymorphism (SSCP) analyses over 2.7 kb of the promoter and all 10 exons (including intron/exon boudaries). The published sequence of the ALR2 gene (GenBank accession no. AF032455; http://www.ncbi.nlm.nih.gov/) was used to design PCR primers to amplify the promoter in nine overlapping fragments and the 10 exons. DNA samples were prepared from peripheral blood leukocytes by the proteinaseK-phenol-chloroform extraction method. The PCR primers and conditions used in the detection of the polymorphisms are available by request.

Direct sequencing
Variant forms of DNA detected by SSCP analysis were identified by direct sequencing of both DNA strands (Thermo Sequenase Radiolabeled Terminator Cycle Sequencing Kit; USB, Cleveland, OH).

Restriction fragment-length polymorphism
The sequence variants were confirmed by restriction fragment-length (RFLP) analysis. The PCR product was digested with the specific restriction enzyme and separated by electrophoresis on an agarose gel. The intron 2 A11370G polymorphism was confirmed by SSCP analysis after direct sequencing because no suitable restriction endonuclease could be used. The previously reported C-106T polymorphism in the promoter area of the ALR2 gene was confirmed by RFLP analysis according to the primers and conditions described by Kao et al. (11). Before enzymatic digestion with BfaI, the PCR product was purified with GFX PCR DNA and the Gel Band Purification Kit (Amersham Pharmacia Biotech, Buckinghamshire, U.K.).

Automated laser fluorescence scanning
The genotyping of the (CA)_n repeat was performed by automated laser fluorescence scanning. PCR primers and conditions were as described by Ko et al. (6). One of the primers was labeled with fluorescent dye during synthesis. After the amplification of the polymorphic DNA fragments, electrophoresis was performed to separate dinucleotide alleles of different sizes, using an automatic laser fluorescence DNA sequencer (ALFexpress; Pharmacia, Uppsala, Sweden) with 6% Hydrolink gels.

Statistical analyses
Statistical calculations were performed using the SPSS/WIN program version 11.0 (SPSS, Chicago, IL), except for the allele frequencies, which were analyzed by two-tailed Fisher’s exact test by StatXact-4 program version 4.0.1 (Cytel Soft-ware, Cambridge, MA). Data are presented as means ± SD, unless otherwise indicated. The differences were evaluated with the ² test, Student’s t test, or nonparametric Mann-Whitney U test. Hardy-Weinberg’s equilibrium was tested by the ² test. General linear model was used when performing adjusted analyses with covariates. The degree of linkage disequilibrium between the –2.1 kb (CA)_n repeat and the C-106T polymorphism was estimated with the computer program EH (Estimation of Haplotype Frequencies; Jurg OH, Rockefeller University) (19). The neurophysiologic parameters and plasma insulin data were analyzed after logarithmic transformation. For technical reasons, complete data were not obtained from all subjects, and the number of diabetic subjects varied slightly between neurophysiologic tests (range for n: 74–85 and 52–83 at baseline and 10-year examinations, respectively).

	RESULTS

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Changes in the neurophysiologic measurements in the nondiabetic subjects were quite modest (18). Therefore, in the present study, only the frequencies of the polymorphisms of the ALR2 gene are reported for the nondiabetic subjects.

Genotyping of the ALR2 gene
A 2.7-kb region of the promoter and all the 10 exons and exon/intron splicing sites of the ALR2 gene were screened in 40 type 2 diabetic patients and 40 nondiabetic control subjects. This identified, after direct sequencing, four DNA sequence variants, three of which have previously been reported: C-106T, C-11G, A11370G (novel), and C19739A (12,13,20) (Table 2). Li et al. (20) recently described a polymorphism at position –12 in the promoter region of the ALR2 gene (C-12G). However, according to the published ALR2 sequence and our repeated calculations, this polymorphism is the same variant we identified at position –11 (C-11G). After performing the RFLP analysis for all of the identified polymorphisms in the whole study population, two of the polymorphisms, C-11G and C19739A, were found to be rare and were not examined further. All the polymorphisms occurred outside the coding region of the gene.

Association analyses
At the baseline examination, diabetic patients with the –106T allele of the C-106T polymorphism were younger (49.5 ± 17.3 vs. 56.7 ± 5.2 years, P = 0.002) and had higher mean body weight (89.1 ± 14.4 vs. 79.4 ± 15.0 kg, P = 0.006) and BMI (31.7 ± 5.0 vs. 29.3 ± 5.0 kg/m², P = 0.042) than the subjects with the C-106C genotype. The sex distribution did not differ between the genotype groups, and no differences in the glucose and insulin levels were found (data not shown).

Neurophysiologic measurements
The subjects with the –106T allele of the C-106T polymorphism had lower sensory RAs in the sural and radial nerves than subjects with the C-106C genotype (Table 3), even after adjustment for age, sex, BMI, and plasma glucose and insulin levels (radial nerve of borderline significance). For the sensory and motor peroneal nerves, RAs tended to be lower in carriers of the T allele (Table 3), but there were no differences in the NCVs.

In a longitudinal analysis over 10 years, diabetic patients with the –106T allele had a larger decrease in the NCV of the motor peroneal nerve as compared with those with the C-106C genotype (–9.4 ± 10.8 vs. –3.5 ± 18.0%, P = 0.016) (Fig. 1), but the difference weakened after adjustment for age, sex, BMI, and glucose and insulin levels (P_a [P adjusted for age, sex, BMI, and fasting plasma glucose and insulin levels] = 0.065). On the contrary, those with the –106T allele had a smaller decrease in the RAs of the sensory peroneal (–29.2 ± 53.9 vs. –55.4 ± 23.8%, P = 0.108, P_a = 0.021), sural (–7.9 ± 62.0 vs. –36.0 ± 50.6%, P = 0.037, P_a = 0.076), and motor peroneal (–6.1 ± 58.2 vs. –27.8 ± 51.4%, P = 0.088, P_a = 0.269) nerves than the patients with the C-106C genotype.

View larger version (47K): [in this window] [in a new window]   Figure 1— Mean 10-year changes (%) in the NCV (A) and RAs (B) among the type 2 diabetic patients according to the C-106T polymorphism of the ALR gene. Pa refers to the P value adjusted for age, sex, BMI, and fasting plasma glucose and insulin values. , C-106C genotype; , C-106T and T-106T genotypes.

The novel intronal A11370G polymorphism of the ALR2 gene was not associated with any of the neurophysiologic parameters measured in the type 2 diabetic subjects (data not shown).

Clinical peripheral neuropathy
At the baseline and 10-year examinations, no associations were observed between any of the polymorphisms examined and clinical signs or symptoms of peripheral neuropathy or the frequency of polyneuropathy among the type 2 diabetic patients (data not shown). At the 10-year examination, those with symptoms of neuropathy (pain or paresthesias) had lower RAs in the sural and sensory peroneal nerves as compared with those with no symptoms (2.3 ± 2.1 vs. 4.2 ± 3.2 µV, P = 0.006, and 1.3 ± 0.9 vs. 1.8 ± 1.1 µV, P = 0.090, respectively), but no differences in NCVs were found.

	CONCLUSIONS

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In the present study, we screened all 10 exons and the promoter region of the ALR2 gene in newly diagnosed Finnish type 2 diabetic patients and nondiabetic control subjects. We were able to find one novel polymorphism in addition to three previously reported ones (11,13,20), none of which occurred in the coding region of the gene. An earlier-described (CA)_n dinucleotide repeat polymorphic marker in the 5'-region of the gene was also investigated (6).

In our study population, the C allele of the previously reported C-106T polymorphism and the Z-2 allele of the (CA)_n repeat marker were found to be more frequent in type 2 diabetic patients than in control subjects, and they were more frequent in our diabetic patients than in most other diabetic populations reported (11–14). In addition, the C and Z-2 alleles were found to be in 60% linkage disequilibrium. It is well known that in different ethnic populations allele frequencies can vary significantly. The Z-2 allele has been found to be in linkage disequilibrium with both the C (11,12) and the T (13,14) alleles of the C-106T polymorphism. Our finding of 60% disequilibrium between the C and Z-2 alleles are in line with those of Kao et al. (11) and Demaine et al. (12).

Basal promoter activity of the human ALR2 gene is located between –192 and +31 upstream of the mRNA capsite (5). The C-106T polymorphism is located proximal to the CCAAT promoter element and may, therefore, have functional significance. This is supported by a recent study in which both the C-11G and C-106T polymorphisms were found to double transcription activities of the ALR2 gene 5' regulatory region (20). Furthermore, in a study by Shah et al. (10), the ALR2 mRNA levels were found to be higher among type 1 diabetic patients with one copy or more of the Z-2 allele of the (CA)_n repeat polymorphism compared with those lacking the Z-2 allele. It is possible, however, that the increased expression of the ALR2 gene observed in the carriers of the Z-2 allele is actually due to the C-106T polymorphism because of known linkage disequilibrium between the two polymorphisms.

Diabetic patients with the T allele of the C-106T polymorphism of the ALR2 gene had lower sensory RAs in the sural and radial nerves and, furthermore, during the 10-year follow-up, a greater decrease in NCV of the motor peroneal nerve but a smaller decrease in the RAs than the subjects with the C-106C genotype. Importantly, no difference in metabolic control was observed between the two diabetic genotype groups during the 10-year follow-up. The Z-2 allele of the (CA)_n repeat polymorphism did not have any consistent association with neurophysiologic measurements.

Early metabolic abnormalities in the nerves of diabetic patients are believed to be due to direct exposure of nerve tissue or its vascular bed to high concentrations of glucose (21), leading to a loss of myelinated fibers and demyelination (22). However, axonal degeneration is another feature of diabetic neuropathy (23), and the reduction of the RAs reflects axonal damage, whereas slowing of NCVs mainly reflects demyelination (18). Therefore, diabetic patients with the T allele of the C-106T polymorphism already had increased axonal degeneration at the time of diagnosis, but further axonal loss is seemingly slow due to the fact that initially low RAs observed in those with the –106T allele were unlikely to decrease further. In addition, the diabetic patients with the –106T allele had a marked decrease in the NCV of the motor peroneal nerve, indicating increased demyelination process. Because nerve ALR2 is expressed in the Schwann cells (24), it might be expected that ALR2 activity is decreased along with the reduction of myelinated fibers. Decreased activity of ALR2 could thus hamper further axonal damage, which could explain these seemingly contradictory results regarding long-term changes in RAs and NCVs. However, the fact that at the 10-year examination no cross-sectional differences in the NCVs or RAs were observed between the two genotype groups could indicate that the C-106T polymorphism of the ALR2 gene increases the risk of peripheral nerve dysfunction early in the course of type 2 diabetes, after which other diabetes-related and environmental factors dilute the relatively small effects of this polymorphism.

Some cross-sectional studies reporting an association between a genetic polymorphism and diabetic peripheral neuropathy exist (7,25), but our study is the first long-term follow-up study applying neurophysiologic measures to demonstrate changes in nervous function in relation to a gene variant. Functional studies of the C-106T polymorphism of the ALR2 gene are needed to elucidate the significance of this gene variant in the process of diabetic neuropathy.

	Acknowledgments

 
This study was supported by the Academy of Finland, The Finnish Cultural Foundation of Northern Savo, and The Finnish Foundation of Diabetes Research.

	Footnotes

 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Received for publication August 6, 2003. Accepted for publication May 8, 2004.

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