Genetic and environmental regulation of Na/K adenosine triphosphatase activity in diabetic patients.
Even if the pathogenesis of diabetic neuropathy is incompletely understood, an impaired Na/K adenosine triphosphatase (ATPase) activity has been involved in this pathogenesis. We previously showed that a restriction fragment length polymorphism (RFLP) of the ATP1-A1 gene encoding for the Na/K ATPase's alpha 1 isoform is associated with a low Na/K ATPase activity in the red blood cells (RBCs) of type 1 diabetic patients. We thus suggested that the presence of the variant of the ATP1A1 gene is a predisposing factor for diabetic neuropathy, with a 6.5% relative risk. Furthermore, there is experimental evidence showing that lack of C-peptide impairs Na/K ATPase activity, and that this activity is positively correlated with C-peptide level. The aim of this study was to evaluate the respective influence of genetic (ATP1-A1 polymorphism) and environmental (lack of C-peptide) factors on RBC's Na/K ATPase activity. Healthy and diabetic European and North African subjects were studied. North Africans were studied because there is a high prevalence and severity of neuropathy in this diabetic population, and ethnic differences in RBC's Na/K ATPase activity are described. In Europeans, Na/K ATPase activity was significantly lower in type 1 (285 +/- 8 nmol Pi/mg protein/h) than in type 2 diabetic patients (335 +/- 13 nmol Pi/mg protein/h) or healthy subjects (395 +/- 9 nmol Pi/mg protein/h). Among type 2 diabetic patients, there was a significant correlation between RBC's Na/K ATPase activity and fasting plasma C-peptide level (r = 0.32, P <.05). In North Africans, we confirm the ethnic RBC's Na/K ATPase activity decrease in healthy subjects (296 +/- 26 v 395 +/- 9 nmol Pi/mg protein/h, r < 0.05), as well as in type 1 diabetic patients (246 +/- 20 v 285 +/- 8 nmol Pi/mg protein/h; P <.05). However, there is no relationship between the ATP1A1 gene polymorphism and Na/K ATPase activity. ATP1A1 gene polymorphism could not explain the ethnic difference. We previously showed that Na/K ATPase activity is higher in type 1 diabetic patients without the restriction site on ATP1A1 than in those heterozygous for the restriction site. This fact was not observed in healthy subjects. In type 2 diabetic patients, association between ATP1A1 gene polymorphism and decreased enzyme activity was found only in patients with a low C-peptide level. Therefore, the ATP1-A1 gene polymorphism influences Na/K ATPase activity only in case of complete or partial C-peptide deficiency, as observed in type 1 and some type 2 diabetic patients, without any correlation with hemoglobin A1c (HbA1c). Correlation observed between C-peptide levels and RBC's Na/K ATPase suggests that the deleterious effect of C peptide deficiency on Na/K ATPase activity is worse in the presence of the restriction site. This may explain the high relative risk of developing the neuropathy observed in type 1 diabetic patients bearing the variant allele.
Jannot
M F
MF
Diabetes Department, University Hospital Timone, Marseille, France.
Raccah
D
D
De La Tour
D Dufayet
DD
Coste
T
T
Vague
P
P
D000328:Adult; D000352:Africa, Northern; D044383:Black People; D002096:C-Peptide / Q000172:deficiency; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics; D004777:Environment; D004912:Erythrocytes / Q000201:enzymology; D005060:Europe; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000097:blood* / Q000235:genetics*; D044465:White People
D002096:C-Peptide; D007527:Isoenzymes; D000254:Sodium-Potassium-Exchanging ATPase