Cystic fibrosis-related diabetes: the role of peripheral insulin resistance and beta-cell dysfunction.

AIMS: The goal of this study was to identify the glycaemic status and investigate the roles of peripheral insulin resistance (IR) and pancreatic -cell dysfunction in the pathogenesis of cystic fibrosis-related diabetes (CFRD) in adult cystic fibrosis (CF) patients with no previous history of glycaemic disturbances. METHODS: The glucose tolerance status of 68 CF patients was determined using 2-h oral glucose tolerance tests (OGTTs). Peripheral IR was measured using the homeostasis model assessment for insulin resistance (HOMA-IR) in the CF group and 46 normal healthy control subjects. Pancreatic -cell function, calculated as the ratio between the 30-min increment in plasma insulin and the corresponding 30-min post-OGTT plasma glucose concentration, was also measured in a subset of 30 CF patients and 16 normal healthy controls. Extended 180-min OGTTs, with frequent plasma glucose and insulin sampling, were also undertaken in 24 CF patients and eight normal healthy controls to determine glucose-induced insulin response. RESULTS: Of the 68 CF patients studied, 41, 18 and nine were found to have normal, impaired and diabetic glucose tolerances, respectively. The mean HOMA-IR values (mU/mmol) in the CF patients, as a whole, were not significantly different compared with the normal healthy controls (CF 2.2 +/- 1.1 vs. control 1.8 +/- 0.9; NS). Within the CF group, glycaemic status had no impact on HOMA-IR (mU/mmol): 2.2 +/- 1.2 (normal glucose tolerance); 2.0 +/- 1.0 (impaired glucose tolerance); and 2.3 +/- 1.1 (diabetic glucose tolerance). -cell function (mU/mmol) was not only significantly lower in the CF group (CF 1.65 +/- 1.8; P < 0.001) but also in the CF group with normal glucose tolerance (2.25 +/- 2.10; P < 0.01) compared with healthy control (4.98 +/- 2.38). Mean plasma glucose concentrations were generally higher and mean plasma insulin concentrations lower in the CF group as a whole when compared with normal healthy controls. Within the CF group, there was a progressive decline in glucose-induced insulin release with worsening glycaemic status. CONCLUSIONS: A lack of difference in peripheral IR, measured using HOMA-IR, in the CF group and healthy controls or within the CF group with differing glycaemic status suggests that IR does not have a significant role in the pathogenesis of CFRD. Pancreatic -cell function, already subnormal in CF patients with OGTT-defined normal glucose tolerance status, deteriorated further with worsening glycaemic status. This suggests that insulinopenia plays a prominent role in the pathogenesis of glucose intolerance and subsequent development of CFRD.

Relation between sodium-lithium countertransport and hypertriglyceridemia in type V hyperlipidemia.

Sodium-lithium countertransport (SLC) kinetics were measured in 30 patients with type V hyperlipidemia, 30 patients with type IIB hyperlipidemia on similar treatment, and 30 age- and sex-matched healthy controls. Clinical and laboratory data including basic anthropometry and blood pressure were obtained and blood was taken for detailed lipid biochemistry, glucose, insulin, and leptin measurements. Patients with type V hyperlipidemia were normotensive but more obese than controls, had elevated triglycerides, very low-density lipoprotein, glucose, and insulin; and reduced HDL cholesterol compared with type IIb controls. The median SLC activity (0.23 v 0.21 mmol Li+/L RBC/h) and median maximal velocity (0.33 v 0.31 mmol Li+/L RBC/h) were increased, but not significantly, compared to controls. In patients with type V hyperlipidemia SLC maximal velocity correlated with log triglycerides (r2 = 0.853; P < .001) and log very low-density lipoprotein (VLDL) triglycerides (r2 = 0.947; P < .001). Sodium-lithium countertransport maximal velocity correlated weakly with the homeostasis model assessment index of insulin resistance (r2 = 0.224; P = .06). The sodium affinity of the transporter did not differ between the groups and was independent of any of clinical or biochemical parameter studied. We conclude that VLDL triglyceride is strongly correlated with SLC maximal velocity and activity in patients with type V hyperlipidemia.

Effects of lipids in patients with familial hypercholesterolaemia on the kinetics of the sodium-lithium countertransporter.

Sodium-lithium countertransport kinetics were measured in 87 patients (50 male; 37 female) with heterozygous familial hypercholesterolaemia (FH) and a group of 38 age range and sex-distribution matched controls. Basic clinical data including basic anthropometry, blood pressure were obtained and blood was taken for detailed lipid biochemistry, glucose and insulin measurement. Patients with FH had elevated total cholesterol, low-density lipoprotein (LDL)-cholesterol and apolipoprotein B concentrations compared to controls. The activity and log transformed maximal velocity (Vmax) of the sodium-lithium countertransporter unlike the affinity (Km) were reduced in patients with FH compared to controls (geometric means 0.172 vs 0.217 mmol Li+/L.RBC.hr; P = 0.02; 0.237 vs. 0.317 mmol Li+/L.RBC.hr; P = 0.009 respectively). In multiple regression analysis, log normalised SLC activity correlated weakly with log triglyceride (beta = 0.225; P = 0.06) and cholesterol (beta = -0.112 P = 0.06). Log Vmax correlated with log triglyceride (beta = 0.307; P = 0.02), and high-density lipoprotein (HDL) (beta = 0.74; P = 0.03) whilst Km correlated with HDL (beta = 1.73; P<0.001) and apoAI (beta = -1.76; P = 0.0048), LDL (beta = -0.14; P = 0.05), and creatine kinase (beta = 0.003; P = 0.01). Cholesterol and triglyceride concentrations rather than insulin resistance seem to be the key features affecting the environmental alteration of sodium lithium countertransporter Vmax in patients with familial hypercholesterolaemia.

Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects.

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.

The role of anxiety and depression in quality of life and symptom reporting in people with diabetes mellitus.

Although quality of life evaluations are widely used throughout medicine, relatively little is known about the psychological processes involved in making these judgements. What is known is that quality of life judgements are not straightforwardly associated with objective measures of health status or clinician ratings. In particular, patient affect appears to be associated with quality of life ratings but whether this relationship is secondary to physical health or not is controversial. The aim of this study was to determine the role of anxiety and depression in the reporting of quality of life in a group of patients with diabetes mellitus. One hundred consecutive patients with diabetes (insulin-dependent diabetes mellitus n = 36 and non-insulin-dependent diabetes n = 64) were assessed using a self-report measure of quality of life, a symptom checklist and a questionnaire measure of anxiety and depression. In addition, they were independently rated for their level of physical impairment. The results showed that depression and, to a lesser extent, anxiety were significantly related to self-reported quality of life even when the differences in physical health and age were controlled for statistically. This study shows that, independent of the level of physical illness, affect, particularly depressive affect, is an important factor in the determination of quality of life.

Pharmacokinetics and absolute bioavailability of oral foscarnet in human immunodeficiency virus-seropositive patients.

The pharmacokinetics, absolute bioavailability, accumulation, and tolerability over 8 days of an oral formulation of foscarnet (90 mg/kg of body weight once daily [QD] [n = 6], 90 mg/kg twice daily [BID] [n = 6], and 180 mg/kg QD [n = 31) were investigated in 15 asymptomatic, human immunodeficiency virus-seropositive male patients free of active cytomegalovirus infection and with normal upper gastrointestinal function. Peak plasma drug concentrations were (mean +/- standard deviation) 46.4 +/- 10.8 microM (90 mg/kg QD), 45.7 +/- 6.9 microM (90 mg/ kg BID), and 64.9 +/- 31.7 microM (180 mg/kg QD) on day 1 and rose to 86.2 +/- 35.8, 78.7 +/- 35.2, and 86.4 +/- 25.0 microM, respectively, on day 8. The mean peak concentration in plasma following the intravenous administration of foscarnet (90 mg/kg) was 887.3 +/- 102.7 microM (n = 13). The terminal half-life in plasma remained unchanged, averaging 5.5 +/- 2.2 h on day 1 (n = 15) and 6.6 +/- 1.9 h on day 8 (n = 13), whereas it was 5.7 +/- 0.7 h following intravenous dosing. Oral bioavailabilities were 9.1% +/- 2.2% (90 mg/kg QD), 9.5% +/- 1.7% (90 mg/kg BID), and 7.6% +/- 3.7% (180 mg/kg QD); the accumulation ratios on the 8th day of dosing were 2.1 +/- 1.1, 1.8 +/- 0.4, and 1.7 +/- 0.7, respectively. The overall 24-h urinary excretion of oral foscarnet averaged 7.8% +/- 2.6% (day 1) and 13.4% +/- 6.0% (day 8), whereas it was 95.0% +/- 4.9% after intravenous dosing. The glomerular filtration rate and creatinine clearance remained constant, and the mean 24-h renal clearances of foscarnet for the entire study group were 96 +/- 18 ml/min (day 1), 88 +/- 13 ml/min (day 8), and 103 +/- 16 ml/min after intravenous dosing. Adverse effects were largely confined to gastrointestinal disturbances, with all subjects experiencing diarrhea that was dose dependent in its severity. The results suggest that the formulation studied would require significant improvement with respect to tolerability and bioavailability to gain clinical acceptance.

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in black normotensive subjects compared with three other ethnic groups.

Sodium-lithium countertransport activity has been proposed as a marker for hypertension and is lower in black compared to Caucasian subjects both with and without vascular disease. The question arises of what is the primary kinetic locus of the altered behaviour of the countertransporter in black subjects and whether this is also seen in normotensive subjects from other non-Caucasian ethnic groups. We studied the sodium-lithium countertransporter in four ethnic groups (black [n = 45], Caucasian [n = 45], Chinese [n = 40], and South Asian [n = 39]) of age-matched normotensive males (age range 18-35 y) with no first-degree family history of hypertension or diabetes. The clinical and laboratory characteristics of the subjects were similar in all four ethnic groups. Minor differences noted were: significantly higher mean height, weight and serum creatinine concentration (P < 0.001) and significantly lower plasma triglyceride concentration (P = 0.02) in the black compared to the other study groups. Sodium-lithium countertransport activity (mmol Li/l RBC h) was significantly lower in the black subjects (0.113 [0.013-0.265]) compared with the other groups (Caucasian, 0.247 [0.037-0.614]; Chinese, 0.210 [0.100-0.707]; South Asian, 0.211 [0.037-0.617]; P < 0.001). No differences were noted between the four study groups in respect of kNa. Mean (s.d.) Vmax values (mmol Li/l RBC h) were also reduced in the black subjects (0.152 [0.088]) compared to the other ethnic groups (Caucasian, 0.376 [0.159]; Chinese, 0.364 [0.182]; South Asian, 0.329 [0.155]; P < 0.001) and there was a strong relationship between countertransport activity and Vmax (r > 0.52; P < 0.001; for each of the study groups). The differences in mean Vmax noted between the Caucasian, South Asian and Chinese subjects were not significant. These results show that, when compared with three other selected ethnic groups, black subjects demonstrate an altered behaviour with respect to Vmax of the sodium-lithium countertransporter, which occurs in the absence of demonstrable vascular pathology.

Characterization of the erythrocyte sodium-lithium countertransporter: limitations and assumptions of traditional and kinetic methodologies.

The present work examined the key elements featuring in the various methods used to characterize the erythrocyte sodium-lithium countertransport. Effects of medium composition on lithium efflux were investigated in 20 subjects. Mean lithium efflux (mmol Li/l RBC.h) into a 150 mM sodium medium was significantly higher than efflux into a revised sodium-rich medium (149 mM) containing 1 mM Mg (0.335 +/- 0.100 vs. 0.298 +/- 0.085 respectively; P < 0.03). Mean lithium efflux into sodium-free media where sodium had been entirely replaced by magnesium, was significantly lower than efflux into a choline-based medium containing only 1 mM magnesium (0.088 +/- 0.027 vs. 0.109 +/- 0.034 respectively; P = 0.03). Sodium-lithium countertransport activity and the transporter's kinetic profile were measured simultaneously in 35 subjects using traditional choline-based and kinetic methodologies. There was a significant correlation between countertransport activity and maximal rate of turnover (Vmax) (r = 0.62; P < 0.001); Vmax values were consistently greater than their corresponding countertransport activities (P < 0.001). On subdividing the subject group into tertiles based on the Michaelis-Menten constant (km) values (mM), < 75, 75-150 and > 150, the slopes of the regression lines for each group diminished progressively (0.64, 0.49 and 0.23 respectively), correlations within each group remained significant (P < 0.001, P < 0.001 and P < 0.02). No significant correlation was found between km values and countertransport activity (r = 0.035; P = NS). Increasing the number of points representing sodium concentrations within the range 0-150 mM, improved the confidence in the emerging estimates of Vmax and km obtained by linear transformation. Comparison of kinetic data derived using four different analytical methods (two linear transformations, a nonlinear regression and a statistical method), showed no significant differences between the estimates yielded for either Vmax (P = 0.88. NS) or km (P = 0.92, NS). This study has highlighted the critical roles of assay conditions and derivation techniques used when measuring sodium-lithium countertransport, emphasizing the need for standardization of the methodology.

Interpractice audit of diagnosis and management of hypertension in primary care: educational intervention and review of medical records.

OBJECTIVE: To determine whether peer review medical audit in a primary care setting changes clinical behaviour in relation to the management of hypertension. DESIGN: Review of medical records in general practices to identify hypertensive patients followed up by assessment of the pre-educational and post-educational management of interventions. SETTING: Six general practices in north west London picked at random within defined criteria of geography and size. SUBJECTS: 740 hypertensive patients managed by 25 different general practitioners. MAIN OUTCOME MEASURES: Improved level of care in terms of better diagnosis by having at least three blood pressure readings before the start of drug treatment, better level of recordings of lifestyle parameters as shown by the level of recordings of body mass index and total lipid values, and better control of blood pressure and harm minimisation as shown by the level of recordings of urea and electrolyte values. RESULTS: Improvement was noted in the level of recordings of body mass index, total lipid concentrations, and urea and electrolyte values but not in better diagnosis or blood pressure control. CONCLUSION: Clinical behaviour of general practitioners can be changed by peer review but more complex behavioural changes which require the cooperation of the patients and cognitive actions by the general practitioners need further investigation.

Renal excretion and pharmacokinetics of foscarnet in HIV sero-positive patients: effect of probenecid pretreatment.

AIMS: The present study was undertaken to test whether the anti-viral agent foscarnet undergoes significant tubular secretion, by using probenecid, an inhibitor of the organic acid secretory pathway in the proximal segment of the nephron. METHODS: The pharmacokinetics and renal excretion of foscarnet (90 mg kg-1 infused over 2 h) have been investigated, in the absence and presence of probenecid pretreatment (1 g twice daily for 3 days) in a group of 10 HIV seropositive patients. RESULTS: Mean (+/-s.d.) peak plasma concentrations were 904 +/- 65 microM (foscarnet) and 862 +/- 97 microM (foscarnet+probenecid) whilst the plasma AUC values were 3326 +/- 451 microM h and 3133 +/- 476 microM h respectively. Terminal elimination half-life remained unchanged at 5.6 +/- 0.7 h and the respective volumes of distribution at steady state were 23 +/- 31 (foscarnet) and 25 +/- 31 (foscarnet+probenecid). Mean total body clearance was 110 +/- 17 ml min-1 (foscarnet) and 113 +/- 13 ml min-1 (foscarnet+probenecid) and the corresponding renal clearances of foscarnet were 102 +/- 5 ml min-1 and 105 +/- 5 ml min-1 respectively. There were no significant differences in the total amount of foscarnet excreted by the kidney with 95 +/- 5% (foscarnet) and 91 +/- 6% (foscarnet+probenecid) of the intravenous dose excreted within 24 h. Glomerular filtration rates at 109 +/- 12 ml min-1 (foscarnet) and 100 +/- 13 ml min-1 (foscarnet+probenecid) and respective creatinine clearances at 120 +/- 15 and 119 +/- 10 ml min-1 remained unchanged throughout the study. CONCLUSIONS: The study shows that foscarnet is not transported via the probenecid-sensitive organic acid secretory pathway in the proximal tubule; the renal elimination of foscarnet is via glomerular filtration.

Kinetic behavior of the erythrocyte sodium-lithium countertransporter in nonnephropathic diabetic twins.

Elevated erythrocyte sodium-lithium countertransport activity occurs in diabetes and may be genetically mediated. The relation of this abnormality to the disease and its complications is unclear. To remove confounding genetic factors and the impact of complications, we studied sodium-lithium countertransport activity together with its kinetic components, maximal rate of turnover (Vmax) and external affinity for sodium (kNa), in identical-twin pairs discordant for insulin-dependent diabetes who were normotensive and had no evidence of nephropathy. Fifteen twin pairs were studied along with the same number of healthy control subjects matched with the twins for gender, age, and body mass index. Clinical and laboratory characteristics of the twins and controls were similar, with the exception that whole blood glucose and glycated hemoglobin concentrations were higher in diabetic twins (P < .001). Comparison of countertransport activity between nondiabetic and diabetic twin groups failed to uncover any significant differences (P = .30, Wilcoxon). Similarly, there were no differences in countertransport activity between the nondiabetic twin group and the controls (P = .38, Mann-Whitney). Furthermore, no associations were noted between residual activity values and residual data of any of the other clinical or laboratory characteristics measured. Comparison of Vmax between nondiabetic and diabetic twin groups showed a significant elevation in the diabetic twins (0.515 + 0.220 v 0.439 + 0.229 mmol Li/L RBC x h, P = .049, paired t test). By contrast, no significant differences were noted between the nondiabetic twin group and the controls (P = .15, unpaired t test). Comparison of kNa between nondiabetic and diabetic twin groups found no significant differences in kNa (P = .42, Wilcoxon). Similarly, there were no differences in kNa between nondiabetic twins and controls (P = .14, Mann-Whitney). Neither the residual data for Vmax nor kNa showed any association with the residual data of any of the other clinical or laboratory characteristics measured. When intertwin correlations were examined, all three parameters describing the behavior of the sodium-lithium countertransporter showed significant intertwin correlations (activity, r = .51, P = .04; Vmax, r = .82, P = .001; kNa, r = .76, P = .001). In conclusion, the diabetic state has a small effect on the Vmax of the sodium-lithium countertransporter. Failure to consider the complex nature of the activity measurement is likely to have been partly responsible for earlier confusion with regard to the effect of diabetes on the countertransporter, since experimental conditions varied between studies and individual kinetic components were not measured. The associations between twins in this study with respect to Vmax and kNa indicate a genetic influence on both constants of the countertransporter. Vmax appears also to be sensitive to certain as yet unidentified environmental factors.

Foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium in HIV-positive patients.

The time course and magnitude of foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium were investigated in 13 male HIV-positive patients who had no active cytomegalovirus-associated disease. The patients had a mean age of 36 years (range 25-49 years) and a mean CD4 cell count of 550 cells/mm3 (range 130-1280 cells/mm3). Peak (mean +/- SD) plasma concentrations of foscarnet (0.89+/-0.10 mmol/l) were seen at the end of the period of drug infusion (90 mg/kg of foscarnet was infused over 2 hours) and declined with a terminal half-life of 5.7+/-0.7 hours. Plasma concentrations of total calcium declined over an 8-hour period, with the lowest concentration occurring after 4 hours (baseline: 2.29+/-0.09 mmol/l; lowest: 2.18+/-0.07 mmol/l; P < 0.001). By contrast, the lowest plasma concentration of ionized calcium occurred after 2 hours (baseline: 1.25+/-0.04 mmol/l; lowest: 0.99+/-0.05 mmol/l; P < 0.001), before gradually recovering to baseline levels over the next 10 hours. The mean maximal decrease in total calcium was 0.11+/-0.06 mmol/l, compared with 0.26+/-0.04 mmol/l for ionized calcium (P < 0.001). Plasma concentrations of total magnesium declined from 0.79+/-0.06 mmol/l (baseline) to 0.74+/-0.04 mmol/l (P < 0.05) after 4 hours and remained at this level after 8 hours. However, plasma concentrations of ionized magnesium fell steeply from 0.56+/-0.03 mmol/l to 0.39+/-0.03 mmol/l at 2 hours (P < 0.001), followed by a gradual recovery over the next 10 hours. The mean maximal decrease in total magnesium was 0.05+/-0.08 mmol/l, compared with 0.18+/-0.03 mmol/l (P < 0.001) for ionized magnesium. In summary, we found that foscarnet-induced changes in the plasma concentrations of total calcium and magnesium were dissociated from the corresponding changes in ionized calcium and magnesium. The maximal decreases in the plasma concentrations of total calcium and magnesium were smaller in magnitude and occurred much later than did the changes in ionized calcium and magnesium. The relative changes in the plasma concentration of ionized magnesium were greater than those of ionized calcium, indicating that foscarnet binds preferentially to the magnesium ion.

Controversies surrounding erythrocyte sodium-lithium countertransport.

BACKGROUND: Interest originally arose in ouabain-insensitive lithium transport across erythrocyte membranes when it was found that lithium could substitute for sodium, either undergoing 1:1 lithium exchange or 1:1 sodium-lithium countertransport in a manner that follows Michaelis-Menten kinetics. Elevation of the sodium-lithium countertransport activity in hypertension was first noted in 1980 and found to be a genetically linked phenomenon. This observation has since been confirmed on several occasions and associations with other diseases such as diabetes have been noted. Nevertheless, many unanswered questions remain about the clinical significance of disturbed sodium-lithium countertransport and its pathological basis. METHODS: Traditional methods for characterizing the sodium-lithium countertransporter have depended on determining differences between lithium fluxes into sodium-rich and sodium-free media. There have been inherent problems in deciding on suitable sodium substitutes. Of the available alternatives, choline has emerged as having advantages over magnesium. Reports in the literature have often failed to take into account varied assay conditions, making comparisons of data from different laboratories difficult. A further complexity has been the realization that sodium-lithium countertransport activity incorporates two key elements in the form of Vmax and k(m). Kinetic studies have shown independent variation in these two parameters with various disease states. RESULTS: Much of the published work to date has continued to rely on measurement of countertransport activity, with magnesium acting as the predominant sodium-substitute. This has occurred despite the undoubted benefits obtained from kinetic analysis. Where kinetics of the sodium-lithium countertransporter have been determined, there have emerged clear associations between Vmax and environmental influences such as plasma lipids with elevated values in dyslipidaemic states including diabetes. The affinity constant, k(m), is more clearly under genetic control and has independent associations with vascular disease. CONCLUSION: Study of the erythrocyte sodium-lithium countertransporter has revealed interesting relationships between altered behaviour of the transporter and specific disease states. Although still somewhat of an enigma, this transporter is emerging as an important membrane constituent whose further study may help us to understand the molecular mechanisms leading to vascular disease.

Angiotensin-converting enzyme (ACE) gene polymorphism and the erythrocyte sodium-lithium countertransporter (SLC) phenotype in hypertension.

It has been suggested that the association between altered behaviour of the erythrocyte sodium-lithium countertransporter (SLC) and hypertension could be secondary to its association with the risk of vascular disease rather than raised blood pressure (BP) per se. Homozygosity for the angiotensin-converting enzyme (ACE) deletion allele has also been linked to a more severe phenotype for cardiovascular disease. The present study investigated whether there is an association between these two indicators of vascular risk in patients with hypertension. The kinetic characteristics of the countertransporter (SLC activity, Vmax and KNa) of patients having the ID ACE-genotype (n = 16) were compared with those patients who had the DD genotype (n = 12). The median (range) SLC activity (mmol Li/l Red Blood Cells.h) in the ID (0.221 [0.061-0.422]) and DD (0.173 [0.094-0.408]) groups were similar (P = 0.28; Mann-Whitney). No significant differences in Vmax (mmol Li/l RBC.h) emerged between the two study groups (0.279 + 0.124 [ID] vs 0.244 + 0.123 [DD]; P = 0.46; unpaired Student's t-test); similarly, no differences emerged between the two groups with respect to KNa (median [range]; ID, 39.8 [12.4-84.4] vs DD, 35.9 [14.6-78.3]; P = 0.47). These data suggest that the SLC phenotype and the ACE-D allele dose are risk factors for cardiovascular disease that function independently of one another.

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in subjects with coronary artery disease.

Sodium-lithium countertransport activity, external affinity for sodium (kNa) and maximal rate of turnover (Vmax), were characterized in 21 male subjects (aged 45 to 65 years) with angiographically proven coronary artery disease; these were compared with a matched group of healthy controls. No significant differences in countertransport activity were noted between the coronary artery disease patients and the healthy controls. By contrast, the median [range] kNa in the coronary artery disease group (8.5 [2.6 to 30.5] mmol/L Na) was significantly lower than that in the controls (59.9 [5.9 to 240.5] mmol/L Na; P < .0001). This reduction was accompanied by a significantly lower mean Vmax (controls 0.403 +/- 0.187 v coronary artery disease group 0.248 +/- 0.121 mmol Li/L RBC/h; P < .01). The findings suggest that disturbed behavior of the sodium-lithium countertransporter is not confined to hypertension but may represent a broader-based membrane dysfunction associated with vascular disease.

Erythrocyte sodium-lithium countertransport activity in non-nephropathic diabetic twins.

OBJECTIVE: It has proved difficult to separate the role of the diabetic state as distinct from its complications in causing the elevation in erythrocyte sodium-lithium (Na-Li) countertransport activity that has been observed in diabetes. The present study sought to isolate the impact of diabetes on the countertransporter by studying groups of non-nephropathic identical-twin pairs both discordant and concordant for diabetes. RESEARCH DESIGN AND METHODS: We studied erythrocyte Na-Li countertransport activity in 49 identical-twin pairs who were discordant for IDDM and 26 identical twin pairs who were concordant for IDDM. Similar numbers of healthy control subjects, matched with the nondiabetic twins from the discordant pairs in respect to sex, BMI, and age were also studied. RESULTS: The clinical and laboratory characteristics of both sets of twins were very similar to those of the control subjects with the exception that whole-blood glucose and glycated hemoglobin concentrations were higher in diabetic twins, whether from discordant or concordant pairs (P < 0.001), and that systolic blood pressure (P < 0.05) and serum HDL cholesterol (P < 0.05) were higher in the discordant diabetic twins than in their nondiabetic co-twins. Median (95% CI) Na-Li countertransport activities (in millimoles of lithium released from 1 liter of erythrocytes per hour) in the nondiabetic discordant twin [0.237 (0.192-0.284)], the diabetic discordant twin [0.284 (0.254-0.326)], and the concordant twin [0.262 (0.207-0.358)] groups were similar to each other and higher than in the control subjects [0.172 (0.138-0.203)]. Countertransport activities in the discordant diabetic twins correlated significantly with their nondiabetic co-twins (r = 0.34; P = 0.015; n = 49), as did those between the concordant diabetic twin pairs (r = 0.68; P < 0.005; n = 26); activity levels were not related to either disease duration or blood glucose control. CONCLUSIONS: An elevation in Na-Li countertransport activity has been noted in non-nephropathic normotensive twin pairs both discordant and concordant for IDDM. The potential genetic contribution to the altered behavior of the countertransporter was similar in both types of twins studied, and individual Na-Li countertransport activities were not significantly related to either duration of diabetes or metabolic control.

Fat arms, obesity and choice of blood pressure cuff size in diabetic patients.

Four hundred consecutive diabetic patients had their mid-arm circumference (AC) measured and body mass index (BMI) calculated to determine the proportion of an unselected clinic group who would require a larger than standard adult blood pressure (BP) cuff and whether or not BMI could be used to predict AC and hence choice of appropriate BP cuff size. More than 75% of both men and women had an AC > or = 29cm, justifying a larger than standard adult cuff for their BP measurement. When patients were classified according to their BMI, at least 80% with a BMI > or = 30 and more than 70% with a BMI of 25-29 had a measured AC > or = 29cm, while less than a third of patients with a BMI > or = 25 had an AC > or = 29cm. These results indicate that, in a diabetic clinic, most patients with a BMI > or = 25 are likely to require an alternative adult BP cuff if their blood pressure is to be measured precisely.