J Korean Diabetes Assoc.  2007 May;31(3):274-283. 10.4093/jkda.2007.31.3.274.

The Association of Aldose Reductase Gene Polymorphisms with Neuropathy in Patients with Type 2 Diabetes

Affiliations
  • 1Department of Internal Medicine, Seoul National University College of Medicine, Korea.

Abstract

BACKGROUND: Previous studies have suggested that polymorphisms in and around the aldose reductase (AR) gene are associated with the development of diabetic microvascular disease. This study explored the hypothesis that the polymorphisms of the (A-C)n dinucleotide repeat sequence, located at 2.1 kilobase (kb) upstream of the transcription start site of AR gene, modulate the risk of diabetic neuropathy (DN).
METHODS
66 patients with DN, 30 without microvascular complications (MC) after 20 years of diabetes, and 87 normal healthy controls were studied. To test highly polymorphic microsatellite marker 2.1 kb upstream of the initiation site of the AR gene, we performed polymerase chain reaction using the primer labeled with fluorescent dye and GeneScan by ABI prism 377 automated DNA sequencer and ABI Genotyper software 2.0.
RESULTS
Seven alleles (Z-6, Z-4, Z-2, Z, Z+2, Z+4 and Z+6) were identified. Z-2 allele was more frequently observed in patients with DN (77.3%) than in those without MC (43.3%, P = 0.007). The subgroup of patients who developed DN within 5 years after the diagnosis of diabetes also had higher frequency of Z-2 allele (91.7%) compared to those without MC (43.3%, P = 0.028). On the contrary, Z+6 allele tended to be more frequent in patients without MC (10.0%) than in those with DN (0%, P = 0.063).
CONCLUSION
These results support the hypothesis that environmental-genetic interactions may modulate the risk of neuropathy in patients with diabetes. Particularly, the Z-2 allele, in the presence of diabetes, may be associated with the development of DN.

Keyword

Diabetic neuropathy; Microsatellite; polymorphism; (A-C)n dinucleotide

MeSH Terms

Aldehyde Reductase*
Alleles
Diabetic Neuropathies
Diagnosis
Dinucleotide Repeats
DNA
Humans
Microsatellite Repeats
Polymerase Chain Reaction
Transcription Initiation Site
Aldehyde Reductase
DNA

Figure

  • Fig. 1 The results of PCR and electrophoresis with 2% agarose gel.

  • Fig. 2 The results of GeneScan by ABI prism 377 automated DNA sequencer and ABI Genotyper software 2.0. The blue-colored peak was the sample labeled FAM and red peakwas internal lane size standard labeled with ROX-500. This example was the homozygote of Z, 23 repeats of (A-C).


Reference

1. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care. 1978. 1:168–188.
2. Dyck PJ, Thomas PK, Asbury AK, Winegard AI, Porte K, editors. Diabetic Neuropathy. 1987. Philadelphia: Saunders.
3. Greene DA, Lattimer SA, Sima AAF. Sorbitol, phosphoinositides and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med. 1987. 316:599–606.
4. Dvornik D. Porte D, editor. Hyperglycaemia in the pathogenesis of diabetic complications. Aldose reductase inhibition: an approach to the prevention of diabetic complications. 1987. New York: McGraw-Hill;7–151.
5. Cameron NE, Cotter MA, Low PA. Nerve blood flow in early experimental diabeties in rats: relation to conduction deficits. Am J Physiol. 1991. 261:E1–E8.
6. Dyck PJ. Hypoxic neuropathy: does hypoxia play a role in diabetic neuropathy? Neurology. 1989. 39:111–118.
7. Nishimura C, Lou MF, Kinoshita JH. Depletion of myo-inositol and amino acids in galactosemic neuropathy. J Neurochem. 1987. 49:290–295.
8. van-Gerven JM, Tjon-A-Tsien AM. The efficacy of aldose reductase inhibitors in the management of diabetic complications. Comparison with intensive insulin treatment and pancreatic transplantation. Drugs Ageing. 1995. 6:9–28.
9. Boel E, Selmer J, Flodgaard JH, Jensen T. Diabetic late complications: will aldose reductase inhibitors or inhibitors of advanced glycosylation end product formation hold promise? J Diabetes complications. 1995. 9:104–129.
10. Baynes JW. Role of oxidative stress in the development of complications of diabetes. Diabetes. 1991. 40:405–412.
11. Corbett JA, Tilton RG, Change K, Hasan KS, Ido Y, Wang JL, Sweetland MA, Lancaster JR Jr, Williamson JR, McDaniel ML. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes. 1992. 41:552–556.
12. Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T, Nyengaard JR, van den Enden M, Kilo C, Tilton RG. Hyperglycaemic pseudohypoxia and diabetic complications. Diabetes. 1993. 42:801–813.
13. Cameron NE, Cotter MA. The relationship of vascular changes to metabolic factors in diabeties mellitus and their role in the development of peripheral nerve complications. Diabetes Metab Rev. 1994. 10:189–224.
14. Raccah D. Physiopathology of diabetic neuropathies. Functional exploration of peripheral involvement. Diabetes Metab. 1998. 24:Suppl 3. 73–78.
15. Yamaoka T, Nishimura C, Yamashita K, Itakura M, Yamada T, Fujimoto J, Kokai Y. Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA. Diabetologia. 1995. 38:255–261.
16. Lee A, Chung SK, Chung SS. Demonstrate that polyol accumulations is responsible for diabetic cataract by the use of transgenic mice expressing aldose reductase gene in the lens. Proc Natl Acad Sci USA. 1995. 92:2780–2784.
17. Dent MT, Tebbs SE, Gonalez AM, Ward JD, Wilson RM. Neutrophil aldose reductase activity and its association with established diabetic microvascular complications. Diabetic Med. 1991. 8:439–442.
18. Ratliff DM, Vander Jagt DJ, Eaton RP, Vander Jagt DL. Increased Levels of Methylglyoxal-Metabolizing Enzymes in Mononuclear and Polymorphonuclear Cells from Insulin-Dependent Diabeitc Patients with Diabetic Complications: Aldose Reductase, Glyoxalase I, and Glyoxalase II. J Clin Endocrinol Metab. 1996. 81:488–492.
19. Shah VO, Dorin RI, Sun Y, Braun M, Zager PG. Aldose reductase gene expression is increased in diabetic nephropathy. J Clin Endocrinol Metab. 1997. 82:2294–2298.
20. Bohren KM, Bullock B, Wermuth B, Gabbay KH. The aldo-keto reductase superfamily. The cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases. J Biol Chem. 1989. 264:9547–9551.
21. Chung S, LaMendola J. Cloning and sequence determination of human placental aldose reductase gene. J Biol Chem. 1989. 264:14775–14777.
22. Graham A, Brown L, Hedge PJ, Gammack AJ, Markham AF. Structure of the human aldose reductase gene. J Biol Chem. 1991. 266:6872–6877.
23. Graham A, Heath P, Morten JE, Markham AF. The human aldose reductase gene maps to chromosome 7q35. Hum Genet. 1991. 86:509–514.
24. Nishimura C, Matsuura Y, Kokai Y, Akera T, Carper D, Morjana N, Lyons C, Flynn TG. Cloning and expression of human aldose reductase. J Biol Chem. 1990. 265:9788–9792.
25. Patel A, Hibberd ML, Millward A, Demaine AG. Chromosome 7q35 and susceptibility to diabetic microvascular complications. J Diabet Complications. 1996. 10:62–67.
26. Shah VO, Scavini M, Nikolic J, Sun Y, Vai S, Griffith JK, Dorin RI, Stidley C, Yacoub M, Vander Jagt DL, Eaton RP, Zager PG. Z-2 microsatellite allele is linked to increased expression of the aldose reductase gene in diabetic nephropathy. J Clin Endocrinol Metab. 1998. 83:2886–2891.
27. Heesom AE, Hibberd ML, Millward A, Demaine AG. A polymorphism in the 5 end of the aldose reductase gene is strongly associated with the development of diabetic nephropathy in type I diabetes. Diabetes. 1997. 46:287–291.
28. Heesom AE, Millward A, Demaine AG. Susceptibility to diabetic neuropathy in patients with insulin dependent diabetes mellitus is associated with a polymorphism at the 5 end of the aldose reductase gene. J Neurol Neurosurg Psychiatry. 1998. 64:213–216.
29. Kao YL, Donaghue K, Chan A, Knight J, Silink M. A novel polymorphism in the aldose reductase gene promoter region is strongly associated with diabetic retinopathy in adolescents with type 1 diabetes. Diabetes. 1999. 48:1338–1340.
30. Donaghue KC, Margan SH, Chan AK, Holloway B, Silink M, Rangel T, Bennetts B. The association of aldose reductase gene (AKR1B1) polymorphisms with diabetic neuropathy in adolescents. Diabet Med. 2005. 22:1315–1330.
31. Ko BC, Lam KS, Wat NM, Chung SS. An (A-C)n dinucleotide repeat polymorphic marker at the 5 end of the aldose reductase gene is associated with early onset diabetic retinopathy in NIDDM patients. Diabetes. 1995. 44:727–732.
32. Imperatore G, Hanson RL, Pettitt DJ, Kobes S, Bennett PH, Knowler WC. Pima Indians Genes Group. Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Diabetes. 1998. 47:821–830.
33. Sivenius K, Pihlajamaki J, Partanen J, Niskanen L, Laakso M, Uusitupa M. Aldose reductase gene polymorphisms and peripheral nerve function in patients with type 2 diabetes. Diabetes Care. 2004. 27:2021–2026.
34. Lahiri DK, Nurnberger JI Jr. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991. 19:5444.
35. Finegold D, Lattimer SA, Nolle S, Bernstein M, Greene DA. Polyol pathway activity and myo-inositol metabolism. A suggested relationship in the pathogenesis of diabetic neuropathy. Metabolism. 1983. 32:988–992.
36. Willars GB, Townsend J, Tomlinson DR, Compton AM, Churchill RD. Studies on peripheral nerve and lens in long-term experimental diabetes: effects of the aldose reductase inhibitor Statil. Metabolism. 1988. 37:442–449.
37. Mizisin AP, Powell HC. Schwann cell injury is attenuated by aldose reductase inhibition in galactose intoxication. J Neuropathol Exp Neurol. 1993. 52:78–86.
38. Vander Jagt DL, Robinson B, Taylor KK, Hunsaker LA. Aldose reductase from human skeletal and heart muscle. Interconvertible forms related by thiol-disulfide exchange. J Biol Chem. 1990. 265:20982–20987.
39. Henry DN, Monte MD, Greene DA, Killen PD. Altered aldose reductase gene regulation in cultured human retinal pigment epithelial cells. J Clin Invest. 1993. 92:617–623.
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