Association of diabetic neuropathy with Na/K ATPase gene polymorphism

Abstract

Neuropathy is a leading cause of disability in diabetes mellitus. Unlike diabetic retinopathy which is an almost constant long-term complication, diabetic neuropathy occurs in only 50 % of cases [1]. This phenomenon is comparable to that observed with diabetic nephropathy [2] which has been associated with genetic susceptibility [3,4]. A number of facts suggest Diabetologia (1997) 40: 506-511 Association of diabetic neuropathy with Na/K ATPase gene polymorphism Summary Diabetes mellitus induces a decrease in Na/K ATpase activity in man and animals, and this decrease plays a role in the development of diabetic neuropathy. Na/K ATPase is encoded by various genes, of which the ATP1 A1 gene is expressed predominantly in peripheral nerves and in erythrocytes. To investigate whether a polymorphism in the Na/K ATPase genes could explain the predisposition of some patients with insulin-dependent diabetes mellitus (IDDM) to develop polyneuropathy, a restriction fragment length polymorphism (RFLP) of the ATP1 A1 gene was studied together with erythrocyte Na/K ATPase activity in 81 Caucasian patients with more than 10 years' duration of IDDM. Associations with diabetic neuropathy, retinopathy and nephropathy were sought. Digestion of the first intron of the ATP1 A1 gene by the Bgl II restriction enzyme revealed a dimorphic allelism. Frequency of the restricted allele was 0.18 in this selected series (however, it was 0.10 in representative samples of IDDM patients and of normal subjects in our area). Mean erythrocyte Na/K ATPase activity was lower in diabetic patients than in 42 control subjects (292 ± 10, vs 402 ± 13 nmol Pi ⋅ mg protein − 1 ⋅ h − 1 , p < 0.0001) and was not related to HbA 1c value or to diabetes duration. It was lower in the group of the 28 patients bearing the restricted allele (241 ± 10 vs 319 ± 11 nmol Pi ⋅ mg protein − 1 ⋅ h − 1 , p < 0.0001).Neuropathy was absent in 50 patients, mild in 15 and severe in 16. When classified accordingly the three groups of patients did not differ with respect to sex, age and duration of diabetes. The respective frequency of the restricted allele among the groups was 10, 73 and 81 %, (p < 0.0001) and mean erythrocyte Na/K ATPase activity was respectively: 322 ± 10.7 nmol Pi ⋅ mg protein − 1 ⋅ h − 1 , 268 ± 15 and 229 ± 17, (p < 0.001). A borderline association between renal status or retinal status and repartition of polymorphism and a borderline correlation between renal status and Na/K ATPase activity were found, but significance disappeared after checking for the presence or absence of neuropathy. IDDM patients bearing the ATP1 A1 variant detected by Bgl II RFLP are much more frequently affected by neuropathy (relative risk 6.5, with 95 % CI 3.3-13). Identification of this risk factor may help to prevent this complication. It is suggested that the restricted allele is in linkage disequilibrium with a genomic mutation allowing diabetes to induce a greater impairment of Na/K ATPase activity which could in turn favour the development of neuropathy. [Diabetologia (199...

Erythrocyte Na/K ATPase activity and diabetes: relationship with C-peptide level

“…In this study, we confirmed our previous finding [3,4,5,6] that diabetic neuropathy is associated with lower erythrocyte Na/K ATPase in Type I diabetic patients. The same finding was also observed in Type II diabetic patients.…”

“…As we showed in previous studies [3,5,6], erythrocyte Na/K ATPase activity is lower in Type I diabetic patients than in control subjects. In the entire group of Type II diabetic patients, mean enzymatic activity was similar to that of control subjects.…”

Risk Factors and Comorbidities in Diabetic Neuropathy: An Update 2015

“…In this context, reduced/impaired Na + /K + -ATPase activity and increased aldose reductase activity may play a supplementary role [97][98][99][100]. Na + /K + -ATPase may be influenced by metabolic control and C-peptide secretion [101].…”

The effect of erythropoietin application on erythrocyte Na,K- ATPase activities in patients with diabetic polyneuropathy

“…These isoforms are coded by different genes due to tissue type and developmental stages. α 1 isoform is commonly exist in peripheral nerves and erythrocytes [3].…”