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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 A 1c (HbA 1c ). 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.

Skeletal muscle energetics of seven hyperthyroid patients were investigated throughout a rest-exercise-recovery protocol using phosphorus-31 magnetic resonance spectroscopy (31P MRS) to quantitatively document in vivo the metabolic bases of impaired muscle performance in hyperthyroidism. The contributions of the main pathways of adenosine triphosphate (ATP) synthesis to energy production and proton efflux were measured and compared with results from normal muscle. At rest, a reduced concentration of phosphocreatine (PCr) was calculated for hyperthyroid patients when compared with controls, whereas pH and concentrations of inorganic phosphate (Pi) and phosphomonoesters (PME) were not different from controls. During exercise, the analysis of changes in pH and PCr concentration demonstrated that (1) at the onset of exercise, the magnitude of glycolysis activation is significantly larger for patients, resulting in a marked pH decrease; (2) the energy cost of exercise is higher for patients as compared with controls performing the same amount of work; and (3) both anaerobic and aerobic pathways are significantly more activated in the hyperthyroid group throughout the 3 minutes of exercise. During recovery, the rates of proton efflux and PCr resynthesis were similar in both groups, excluding any alteration in oxidative function and proton handling as a cause of initial glycolytic hyperactivation. The increased energy cost measured for patients during exercise evidences an increased need for energy, which is (1) probably linked to the existence of additional ATP-consuming mechanism(s), and (2) supported by hyperactivation of both aerobic and anaerobic pathways. These findings imply that, all things equal, a hyperthyroid muscle requires more energy to function than normal, and as a result is potentially more fatiguable.

This study was undertaken to obtain further information on the mechanism by which blood fibrinolytic activity, a balance between plasminogen activators and inhibitors, is lowered in obese subjects. Fasting blood samples were collected from 35 subjects, aged 15 to 45 years, with normal glucose tolerance and a Body Mass Index (BMI) varying widely between 16 and 45 (normal, 19 to 25). Euglobulin Fibrinolytic Activity (EFA) did not correlate with the level of tissue type plasminogen activator (t-PA) related antigen but exhibited a negative correlation with the level of PA inhibitor (r = −.609, P < 0.01). EFA was negatively and PA inhibitor positively correlated with both BMI (r = −.381, P < 0.02 and .664, P < 0.01, respectively) and plasma insulin level (r = .410, P < 0.02 and .521, P < 0.01, respectively). Stepwise analysis showed that these correlations were independent. As expected, plasma insulin was correlated with BMI (r = .512, P < 0.01) and triglyceride level (r = .38, P < 0.02), total cholesterol with age (r = .379, P < 0.02). Ten obese subjects were submitted to a 24-hour fast. While body weight did not change appreciably, plasma insulin decreased from 22.3 ± 2.2 to 16.3 ± 1.1 μU/ml, EFA increased from 3.6 ± .8 to 4.9 ± .67 mm, and PA inhibitor decreased from 4.52 ± .76 to 3.44 ± .63 IU/mL. All these differences were significant. T-PA-related antigen did not change. These results suggest that PA inhibitor plays a major role in the regulation of fibrinolysis in healthy subjects and that high plasma insulin levels may be responsible for low fibrinolysis through high levels of PA inhibitor in obese subjects.

Epidemiologic data strongly suggest that upper distribution of body fat and high plasminogen activator inhibitor (PAI) activity are risk factors for cardiovascular disease. Therefore, a link between these two parameters was evaluated by studying 51 menstrually active nondiabetic obese women. In this group positive correlations were observed between body mass index (BMI), waist to hip circumference ratio (W/H ratio, which estimates body fat distribution), plasma insulin, and PAI activity. In addition, plasma triglycerides were related to the W/H ratio and insulin and PAI activity. Partial correlations revealed that BMI was independently and solely related to W/H ratio, which was also independently related to plasma insulin, which in turn related to PAI activity. These results suggest that upper body fat distribution acts as a risk factor of cardiovascular disease through its association with high PAI activity.