The role of ion content and cell volume in insulin action.
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Animals↗
Biomedical subjects
T H Thomas
Publications and source records attributed to T H Thomas.
Nephropathy and changes in sodium-lithium countertransport kinetics in type 2 (non-insulin-dependent) diabetes mellitus.
Previous studies of erythrocyte sodium-lithium countertransport activity, a putative genetic marker of essential hypertension, in Type I and Type II diabetic patients with nephropathy have given conflicting results. We have found changes in the maximum velocity (Vmax) and sodium-affinity constant (Km) of sodium-lithium countertransport in Type I diabetic patients with diabetic nephropathy. In this study, sodium-lithium countertransport kinetics were measured in Type II diabetic patients with established diabetic nephropathy, matched uncomplicated Type II diabetic patients, non-diabetic patients with nephropathy and healthy control subjects. Mean standard sodium-lithium countertransport activity was not significantly increased in either of the groups of diabetic patients compared with the non-diabetic control groups. The Type II diabetic patients with nephropathy had a significantly reduced km and Vmax compared with the uncomplicated diabetic patients and non-diabetic control group. These kinetic changes are identical to those observed in Type I diabetic nephropathy patients. There are similar underlying changes in the erythrocyte plasma membrane with the development of nephropathy in both Type I and Type II diabetes.
Antiporters↗
Characterization of the response of erythrocyte sodium-lithium countertransport to inhibitors.
To clarify the biochemical characteristics of the sodium-lithium countertransporter (SLC) the responses of SLC to two probes of ion transport--4,4'-diisothiocyanostilbene-2,2' disulfonate, and N-ethylmaleimide--were assessed. The results suggest that the SLC transporter is associated with the band 3 protein in the plasma membrane and demonstrate that a sulfhydryl group is essential for transport function.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Erythrocyte sodium-lithium countertransport activity and total body insulin-mediated glucose disposal in normoalbuminuric normotensive type 1 (insulin-dependent) diabetic patients.
Insulin resistance in Type 1 (insulin-dependent) diabetes mellitus may be associated with raised erythrocyte sodium-lithium countertransport activity in patients with hypertension, or nephropathy, or both. However, in these circumstances it is difficult to separate the impact of hypertension, hyperlipidaemia and nephropathy on erythrocyte sodium-lithium countertransport from that of insulin resistance. We have therefore examined the relationship between insulin-mediated glucose disposal and erythrocyte sodium-lithium countertransport in 41 normotensive (mean blood pressure 120/74 mmHg), normoalbuminuric (mean albumin excretion 6.2 micrograms/min), normolipidaemic (mean serum cholesterol 4.3 mmol/l and mean serum triglycerides 1.0 mmol/l) Type 1 diabetic patients. Erythrocyte sodium-lithium countertransport was on average 0.31 mmol Li.h-1.l erythrocytes-1 (range 0.07-0.69). Nine patients had values above 0.40 mmol Li.h-1.l erythrocytes-1 (0.51 +/- 0.10 mmol Li.h-1.l erythrocytes-1). The patients with high erythrocyte sodium-lithium countertransport were matched for age, sex, BMI, HbA1 and duration of diabetes, with nine patients with normal erythrocyte sodium-lithium countertransport. Insulin-mediated glucose disposal was evaluated during the last hour of a euglycaemic clamp (insulin 0.015 U.kg-1.h-1; blood glucose clamped at 7.0 mmol/l). The free insulin levels were comparable between the patients with high and normal erythrocyte sodium-lithium countertransport (37.2 +/- 14.7 mU/l and 34.7 +/- 17.2 mU/l respectively). Insulin-mediated glucose disposal was on average 3.1 +/- 1.5 (range 0.8-6.8) mg.kg-1.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Sodium-lithium countertransport activity is not affected by short-term insulin exposure in vivo or in a physiologic medium in vitro.
This study examined the acute effects of physiologic concentrations of insulin in vitro and in vivo on sodium-lithium countertransport (SLC) kinetics in nondiabetic subjects. SLC was measured at eight different external sodium concentrations including the standard 150 mmol/L, allowing calculation of both maximal velocity (Vmax) and external sodium affinity (Km). Incubation with insulin (50 mU/L) in 110 MgCl2 but not in 150 mmol/L NaCl decreased standard SLC activity. The decrease was accounted for by a reduction in Vmax, whereas Km remained constant. There was no difference in standard SLC activity, Vmax, or Km when endogenous insulin concentrations were altered either by fasting or by a carbohydrate load. Similarly, standard SLC activity, Vmax, or Km were not significantly different before or at the completion of a euglycemic hyperinsulinemic clamp. These findings provide no support for an action of physiologic concentrations of insulin either in vitro or in vivo on the kinetics of the countertransporter measured in vitro in isotonic sodium-containing media.
Adult↗
The effect of short-term low-dose cyclosporin on renal function and blood pressure in patients with psoriasis.
The effect of short-term (mean 2.4 months), low-dose (5 mg/kg) cyclosporin A (CyA) on renal function and blood pressure was studied in eight patients with psoriasis. Studies were undertaken before, during and after treatment. Glomerular filtration rate (GFR) post-treatment was significantly higher than pretreatment or during treatment (pre, 119 +/- 7; during, 113 +/- 9; post, 133 +/- 11 ml/min per 1.73 m2; pre vs. during, NS; during vs. post, P < 0.01; pre vs. post, P < 0.05); effective renal plasma flow (ERPF) was unchanged (pre, 515 +/- 38; during, 485 +/- 49; post, 560 +/- 45 ml/min per 1.73 m2). There was no change in the urinary excretion of either albumin or the enzymes N-acetyl-glucosaminidase, lactate dehydrogenase, alanine aminopeptidase and alkaline phosphatase. There was a decrease in exchangeable sodium which persisted post-treatment (pre, 56 +/- 3; during, 49 +/- 3; post, 49 +/- 3 mmol/kg LBM; pre vs. during, P = 0.07; during vs. post, NS; pre vs. post, P = 0.06). Blood pressure assessed as either a single reading, or the mean of a 24 h ambulatory recording, increased during treatment (single reading: pre, 113/73; during, 126/83; post, 114/70 mmHg; mean 24 h: pre, 114/71; during, 123/76; post, 120/72 mmHg). Thus, short-term use of CyA at a dose of 5 mg/kg for the treatment of psoriasis is associated with a significant increase in blood pressure, but only a transient mild reduction in GFR, which did not reach significance.
Adult↗
Increased human erythrocyte sodium-lithium countertransport in hyperlipidaemic patients may indicate increased membrane lipid fluidity.
Erythrocyte sodium-lithium countertransport (SLC) activity, membrane fluidity, plasma triglyceride and cholesterol were measured in hyperlipidaemic patients and normal subjects. Fluidity was assessed by the fluorescence anisotropy (inversely related to fluidity) of the probes 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1,4-trimethylammonium-3,5-hexatriene (TMA-DPH). In a second group of patients the maximum velocity (Vmax) and external sodium affinity constant (km) of SLC was also measured. In the first group of patients, SLC activity was increased compared with the controls (0.279 +/- 0.019 vs. 0.213 +/- 0.013, P = 0.006) as was membrane fluidity in the deep hydrophobic regions (DPH anisotropy 0.211 +/- 0.0007 vs. 0.215 +/- 0.0011, P = 0.007). There was a strong correlation between SLC and DPH anisotropy (Rs = -0.72, P = < 0.001) which was due to the correlation between Vmax and DPH anisotropy (Rs = -0.90, P = < 0.001). Increases in Vmax of SLC in hyperlipidaemic patients may be due to differences in lipid organisation in the deep hydrophobic regions of the membrane which may affect the turnover rate of the transporter.
Adult↗
Increased red cell sodium lithium countertransport activity, total exchangeable sodium, and hormonal control of sodium balance in normoalbuminuric type 1 diabetes.
The relationship between erythrocyte sodium lithium countertransport activity (SLC), total exchangeable sodium (NaE), and hormonal control of renal function was examined in 40 normotensive, normoalbuminuric, non-neuropathic Type 1 diabetic subjects, of whom 8 had elevated SLC (> 0.40 mmol Li h-1l-1 rbc). Eleven health controls with normal SLC, who were of comparable age, body mass, and blood pressure were also studied. By contrast with healthy controls, SLC in Type 1 diabetes was not associated with plasma renin activity (PRA), aldosterone, systolic blood pressure or lean body mass. SLC was also unrelated to atrial natriuretic peptide (ANP) (Type 1 diabetes only) and NaE. NaE was not correlated with any other variables. The relationships between PRA and aldosterone in healthy controls were retained in Type 1 diabetes (R2 0.37 supine, p = 0.00001, and 0.27 ambulant, p = 0.0005), as were respective direct and inverse relations between vasopressin and ANP and both PRA (rs 0.54 to 0.57, rs -0.43 to -0.53), and aldosterone (rs 0.78 to 0.80, rs -0.71 to -0.80). Fasting free serum insulin and vasopressin were both inversely related to ANP (rs -0.91 and -0.71, respectively). In the absence of autonomic dysfunction, hypertension or early nephropathy in Type 1 diabetes, increased SLC or exchangeable sodium were unrelated to each other or with hormonal control of sodium balance, but the homeostatic factors controlling hormonal interaction appear to be maintained. The interaction between insulin and hormonal control of sodium and water balance may be modified by circulating free insulin concentrations.
Adolescent↗
Erythrocyte sodium lithium countertransport in normal and hypertensive pregnancy: relation to haemodynamic changes.
OBJECTIVE: To establish the changes in erythrocyte sodium lithium countertransport (SLC) with advancing normal pregnancy and to determine if these changes were different in pregnancy induced hypertension (PIH). The changes in both groups were assessed in relation to haemodynamic changes. DESIGN: SLC, mean arterial pressure (MAP), cardiac output (CO) and total peripheral vascular resistance (TPVR) were determined serially during normal pregnancy and cross-sectionally in PIH. Women were studied again 20 weeks after delivery where possible. SETTING: Routine antenatal clinic and antenatal ward of a regional reference centre. SUBJECTS: Fifty-one normal primigravid women were studied serially and 41 primigravid women with PIH were studied at time of diagnosis. RESULTS: During normal pregnancy SLC (mmol Li/h/l cells) increased from a nonpregnant value of 0.24 +/- 0.02 (mean +/- SEM) to 0.32 +/- 0.02 at 14 weeks, and 0.37 +/- 0.02 at 20 weeks gestation. This was maintained until 38 weeks (0.40 +/- 0.02). The increase until 20 weeks occurred at the time of greatest change in CO (5.10 +/- 0.18 to 6.79 +/- 0.20 l/min) and TPVR (1327 +/- 58 to 969 +/- 33 dyn/s/cm-5). The decrease in TPVR with a rise in SLC is opposite to the relation reported in essential hypertension so that a functional relation is unlikely. However, the changes within pregnancy were positively correlated (r = 0.43, P < 0.01). In hypertensive pregnancies TPVR was elevated compared with normotensive pregnancies (1543 +/- 100 vs 1090 +/- 37) but the SLC was not different from that found in normotensive pregnancies (0.43 +/- 0.02 vs 0.40 +/- 0.02). CONCLUSIONS: The changes in SLC activity suggest dynamic effects on erythrocyte membrane function during pregnancy. However, no differences could be found between normal and hypertensive pregnancy and SLC is unlikely to be of value as a marker of hypertensive risk during pregnancy.
Adult↗
Alterations in erythrocyte chloride content accompanying the changes in erythrocyte hydration and potassium content in normal human pregnancy: a comparison with pregnancy induced hypertension.
OBJECTIVES: To determine whether the change in erythrocyte potassium content in normal human pregnancy is accompanied by a similar change in erythrocyte chloride content. To assess erythrocyte hydration and potassium and chloride content in pregnancies complicated by proteinuric pregnancy induced hypertension. DESIGN: A serial study during and after normal pregnancy. A comparative study during and after pregnancies complicated by proteinuric pregnancy induced hypertension (PIH). Erythrocyte hydration, total osmoles, potassium and chloride and plasma osmolality were determined. SETTING: University teaching hospital, UK. SUBJECTS: Twenty-eight women studied at 14, 28 and 36 weeks of normal pregnancy and ten women with PIH studied during the third trimester of pregnancy. All women were reinvestigated 20 weeks after delivery. RESULTS: The fall of erythrocyte potassium early in normal pregnancy (277.4 vs 265.2 mmol/kg; P < 0.02) and its rise between 28 and 36 weeks (272.3 vs 288.0 mmol/kg; P < 0.005) were accompanied by similar changes in erythrocyte chloride content (151.9 vs 131.1 mmol/kg; P < 0.001 and 129.4 vs 141.3 mmol/kg; P < 0.001, respectively). Plasma osmolality in PIH was raised above that normal in pregnancy (287.2 vs 283.0 mosm/kg; P < 0.005). In PIH, compared to normal pregnancy, erythrocyte hydration (2.00 vs 1.89 l/kg dry weight cells), total osmoles (573.0 vs 534.2 mosm/kg), potassium (303.0 vs 288.0 mmol/kg) and chloride (154.9 vs 141.3 mmol/kg) were greater. CONCLUSIONS: These findings further support the hypothesis that changes in plasma osmolality in pregnancy are secondary to alterations in cell osmoles and serve to limit changes in cell hydration. Erythrocyte composition and plasma osmolality are altered in PIH.
Chlorides↗
Serum triglyceride and insulin levels are associated with erythrocyte sodium-lithium counter-transport activity in normoglycaemic individuals.
The relationship between erythrocyte sodium-lithium counter-transport activity, serum insulin, lipids and demographic factors was examined in 93 normoglycaemic predominantly normotensive individuals with mild fasting hypercholesterolaemia (greater than 5.2 mmol/l). The major significant univariate correlates of sodium-lithium counter-transport activity were fasting serum triglycerides, HDL cholesterol, the ratio of fasting glucose: insulin, apo A1, alcohol consumption and apo B. Stepwise multiple regression analysis revealed 24% of the variability in sodium-lithium counter-transport activity could be accounted for by independent contributions of fasting serum triglycerides, alcohol consumption, the fasting glucose/insulin ratio and apo A1 and ANOVA confirmed a significant relationship with fasting insulin measures that was independent of serum triglycerides (P less than 0.05). The relationship between erythrocyte sodium-lithium counter-transport activity and concentrations of serum triglycerides, HDL components, insulin and additionally alcohol consumption, could reflect the influence of those variables on erythrocyte structure and function.
Alcohol Drinking↗
The role of cell swelling in the stimulation of glycogen synthesis by insulin.
In hepatocyte cultures, insulin stimulates cellular accumulation of K+, partly (approximately 20%) by net replacement of cell Na+, but largely (approximately 80%) by increasing the cell K++Na+ content, with a consequent increase in cell volume. An increase in cation content occurred within 5 min of exposure to insulin and was not secondary to metabolic changes. Insulin also increased the cation content, by increasing the Na+ content, in a K(+)-free medium or when K+ uptake was inhibited with 1 mM-ouabain. However, insulin did not increase the cation content in a Na(+)-free medium. The stimulation of glycogen synthesis by insulin, like the increase in cation content, was blocked in a Na(+)-free medium, but not when K+ uptake was inhibited. Hypo-osmotic swelling restored the stimulation of glycogen synthesis in a Na(+)-free medium, indicating that the lack of effect of insulin in the iso-osmotic Na(+)-free medium was not due to a direct requirement for Na+ for glycogen synthesis, but to a secondary mechanism, dependent on Na+ entry, that can be mimicked by hypo-osmotic swelling. Quinine increased cell volume further and caused a further increase in glycogen synthesis. The hypothesis that cellular uptake of K+ may be part of the mechanism by which insulin controls metabolism was discounted, because inhibition of K+ uptake does not block the metabolic effects of insulin [Czech (1977) Annu. Rev. Biochem. 46, 359-384]. The present results support the hypothesis that an increase in cell cation content, and thereby cell volume, rather than K+ uptake, is part of the mechanism by which insulin stimulates glycogen synthesis in hepatocytes.
Amino Acids↗
Kinetics of sodium-lithium countertransport activity in patients with uncomplicated type 1 diabetes.
1. Increased erythrocyte sodium-lithium countertransport activity has been reported to be associated with nephropathy in type 1 diabetes and linked to a family history of essential hypertension. 2. This study aimed to determine the mechanism of increased sodium-lithium countertransport activity. Sodium-lithium countertransport kinetics were measured in uncomplicated and hyperlipidaemic type 1 diabetic patients. 3. In the nine out of 31 uncomplicated type 1 diabetic patients who had high sodium-lithium countertransport activity, the sodium affinity (Km) was normal but the maximum velocity (Vmax) was increased. 4. Hyperlipidaemia, when present in diabetic patients, was associated with increased sodium-lithium countertransport activity, but could not explain the high activity in uncomplicated type 1 diabetic patients in whom plasma lipid concentrations were normal. 5. Sodium-lithium countertransport activity is increased in type 1 diabetes by a mechanism different to that in essential hypertension, where the mechanism is a low Km (increased sodium affinity). Hence familial hypertension cannot explain the raised sodium-lithium countertransport activity in type 1 diabetes.
Adult↗
Changes in erythrocyte sodium-lithium countertransport kinetics in diabetic nephropathy.
1. It has been proposed that raised erythrocyte sodium-lithium countertransport activity in type 1 diabetic patients is associated with an increased risk of developing diabetic nephropathy. Diabetic patients with established nephropathy would therefore be expected to have high activity. 2. Standard sodium-lithium countertransport activity, sodium affinity (Km) and maximum velocity (Vmax) were measured in type 1 diabetic patients at different stages of diabetic nephropathy and in appropriately matched uncomplicated diabetic patients and normal control subjects. 3. A small proportion (15%) of patients with nephropathy had standard sodium-lithium countertransport activity higher than the control range. However, mean standard sodium-lithium countertransport activity in the diabetic patients with nephropathy [mean +/- SEM, 0.26 +/- 0.12 mmol of Li+ h-1 (l of cells)-1] was not significantly higher than in the uncomplicated diabetic patients [0.27 +/- 0.03 mmol of Li+ h-1 (l of cells)-1] or in the normal control subjects [0.25 +/- 0.02 mmol of Li+ h-1 (l of cells)-1]. 4. There were marked changes in the kinetic characteristics of the sodium-lithium countertransport in the diabetic patients with nephropathy so that there were decreases in both Km and Vmax. 5. These kinetic changes could not be attributed to an effect of either renal failure per se or the duration of diabetes. 6. The characteristic kinetic changes in sodium-lithium countertransport may indicate underlying alterations in membrane function with the onset of nephropathy in type 1 diabetes.
Antiporters↗
Erythrocyte sodium-lithium countertransport: clinically useful, pathophysiologically instructive or just phenomenology?
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Antiporters↗
Reduced erythrocyte and leukocyte magnesium is associated with cyclosporin treatment and hypertension in renal transplant patients.
Plasma, urine, erythrocyte and leukocyte magnesium were measured in normotensive and hypertensive renal transplant patients who were being treated with either azathioprine or cyclosporin. These were compared with essential hypertensive patients and normal subjects. Erythrocyte and leukocyte magnesium were reduced in renal transplant patients in independent association (ANOVA) with both cyclosporin treatment (P = 0.03, P = 0.016 respectively) and hypertension (P less than 0.001 for both). Therefore, hypertensive transplant patients on cyclosporin had the lowest magnesium content of both erythrocytes (1.22 +/- 0.09 mmol/l cells) and leukocytes (2.68 +/- 0.2 nmol/10(6) cells) compared to normal subjects (1.96 +/- 0.17 and 4.11 +/- 0.58 respectively) whereas normotensive transplant patients on azathioprine had normal values (2.12 +/- 0.16 and 5.13 +/- 1.0 respectively). Plasma magnesium was also reduced with cyclosporin treatment. Urine magnesium was not significantly different between any of the groups. Therefore, magnesium depletion may have a role in hypertension in renal transplant patients. Since cyclosporin treatment is also associated with magnesium depletion, this could explain the increased occurrence of hypertension in these patients.
Adult↗
Plasma lipids affect maximum velocity not sodium affinity of human sodium-lithium countertransport: distinction from essential hypertension.
Inheritance is a major determinant of increased sodium-lithium countertransport (SLC) activity in hypertension. However, hyperlipidaemia can also cause increased SLC activity in some individuals and it is difficult to distinguish this effect from the effect of hypertension. Erythrocyte SLC activity and its kinetic determinants sodium affinity (km) and maximum velocity (Vmax) were measured in 25 hyperlipidaemic patients and 15 normal controls (NC). Increased SLC activity (0.31 +/- SEM 0.03 mmol Li/(h x 1 cells) vs. NC 0.20 +/- 0.01, P < 0.01) in the hyperlipidaemic patients was associated with increased Vmax (0.59 +/- 0.07 vs. NC 0.41 +/- 0.03, P < 0.01) but normal km (median 120 range [40-324] mmol l-1 vs. 140 [108-260]. Lipid-lowering therapy resulted in decreased SLC activity secondary to a fall in Vmax. Km remained constant despite the changes in lipids and Vmax. The mechanism of increased SLC activity in hyperlipidaemia is different from that in essential hypertension where increased sodium affinity is found. Measurement of the kinetic characteristics of SLC may discriminate between the independent influences of hypertension and hyperlipidaemia on the sodium-lithium countertransporter.
Adult↗
Sodium-lithium countertransport kinetics in normal and hypertensive human pregnancy.
Erythrocyte sodium-lithium countertransport activity is increased in a subgroup of patients with essential hypertension but activity also rises temporarily during normal pregnancy. It is not known if the mechanism of raised activity is the same in both of these situations. Standard sodium-lithium countertransport activity and its kinetic characteristics (sodium affinity and maximum velocity) were measured in 15 women with a normal pregnancy. The mechanism of raised sodium-lithium countertransport activity was an increase in maximum velocity. There was no change in sodium affinity. This contrasts with essential hypertension where the mechanism is increased sodium affinity. Sodium-lithium countertransport activity was also measured in 14 primigravidae whose pregnancies were complicated by hypertension, and mean activity was not significantly higher than in normal pregnancy. However, six women had increased sodium affinity suggestive of essential hypertension and a different underlying mechanism of hypertension to those with normal sodium affinity. Prospective measurement of sodium-lithium countertransport kinetics may lead to a better understanding of the pathophysiology of hypertension in pregnancy.
Adult↗