Genetic and environmental regulation of Na/K adenosine triphosphatase activity in diabetic patients

• Published in: Metabolism, clinical and experimental Vol. 51; no. 3; pp. 284 - 291
• Main Authors: Jannot, M.F., Raccah, D., De La Tour, D.Dufayet, Coste, T., Vague, P.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2002; Elsevier
• Subjects: Adult; Africa, Northern; African Continental Ancestry Group; Associated diseases and complications; Biological and medical sciences; C-Peptide - deficiency; Diabetes Mellitus - enzymology; Diabetes Mellitus - genetics; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Environment; Erythrocytes - enzymology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Europe; European Continental Ancestry Group; Female; Humans; Isoenzymes - blood; Isoenzymes - genetics; Male; Medical sciences; Middle Aged; Polymorphism, Genetic - physiology; Sodium-Potassium-Exchanging ATPase - blood; Sodium-Potassium-Exchanging ATPase - genetics; Africa, Northern; Europe; Endocrinopathy; Human; Immunopathology; Nervous system diseases; Adenosine; Correlation; Peptides; Enzyme; Pathogenesis; Deficiency; Adenosinetriphosphatase; Red blood cell; Autoimmune disease; Environmental factor; Neuropathy; Non insulin dependent diabetes; Variant; Regulation(control); Restriction fragment length polymorphism; Gene; Risk factor; Insulin dependent diabetes; Hydrolases; Genetics
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1053/meta.2002.29009

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 [plusmn] 8 nmol Pi/mg protein/h) than in type 2 diabetic patients (335 [plusmn] 13 nmol Pi/mg protein/h) or healthy subjects (395 [plusmn] 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 [lt ] .05). In North Africans, we confirm the ethnic RBC's Na/K ATPase activity decrease in healthy subjects (296 [plusmn] 26 v 395 [plusmn] 9 nmol Pi/mg protein/h, r [lt ] 0.05), as well as in type 1 diabetic patients (246 [plusmn] 20 v 285 [plusmn] 8 nmol Pi/mg protein/h; P [lt ] .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.