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Intracellular pH, intrauterine growth and the insulin resistance syndrome
J H Pinkney1, P Vernon, E Carstensen
1Department of Medicine, Clinical Sciences Centre, University Hospital, Aintree, Liverpool, UK.
Insights
Sodium transport defects are linked to heart disease risk. This study found red blood cell sodium-lithium countertransport (SLC) relates to insulin resistance, while low intracellular pH is linked to low birth weight and adult insulin resistance.
Area of Science:
- Cardiovascular Science
- Metabolic Syndrome Research
- Developmental Origins of Health and Disease (DOHaD)
Background:
- Defects in sodium-hydrogen exchange (NHE) and sodium-lithium countertransport (SLC) are associated with increased coronary heart disease (CHD) risk.
- Sodium transport mechanisms are implicated in cellular regulation, potentially explaining links to CHD.
- Impaired early-life growth is also linked to adult CHD, with 'programmed' cellular alterations proposed as a mechanism.
Purpose of the Study:
- To investigate if birth anthropometry predicts adult sodium-hydrogen exchange (NHE) or sodium-lithium countertransport (SLC).
- To examine the association between NHE and SLC in adults with insulin resistance syndrome (IRS) variables.
- To explore potential 'programmed' cellular phenotypes linking early development to adult cardiovascular and metabolic health.
Main Methods:
- Red blood cell SLC activity was measured in 26 adults.
- Sodium-hydrogen exchange (NHE) kinetics (Vmax, Km, Hill coefficient) were measured in dermal fibroblasts from 15 subjects.
- Subjects were characterized anthropometrically at birth and assessed for IRS variables in adulthood.
Main Results:
- Red cell SLC activity correlated with LDL cholesterol, triglycerides, and urate, but not with birth anthropometry.
- NHE Vmax correlated significantly with plasma insulin, but birth weight was not related to NHE kinetics.
- Intracellular pH (pHi) showed significant correlations with birth weight, insulin sensitivity, fasting glucose, 2-hour insulin, and 2-hour glucose levels.
Conclusions:
- Red cell SLC is associated with adult insulin resistance syndrome variables but not with birth weight.
- Low intracellular pH (pHi) is linked to both low birth weight and adult insulin resistance.
- This suggests intracellular pH may represent a 'programmed' cellular phenotype, though not explained by altered NHE kinetics.
Abstract:
Defects of both sodium-hydrogen exchange (NHE) and sodium-lithium countertransport (SLC) have been described in subjects at increased risk of coronary heart disease (CHD). Sodium transport is linked to the regulation of cell volume, intracellular pH and cell growth, which may explain aspects of this association. However, impaired growth in early life is also linked to adult CHD, and 'programmed' alterations of cell behaviour are postulated to be responsible for this. In this study, therefore, we examined whether NHE or SLC in adults are predicted by anthropometric measures at birth, as well as being associated with insulin resistance syndrome (IRS) variables in adulthood. Red cell SLC was measured in 26 adults, and NHE in dermal fibroblasts from another 15 subjects characterized anthropometrically at birth. SLC activity correlated with LDL cholesterol, triglycerides and urate (r=0.42 - 0.49; 0.05 > P>0.01), but not birth anthropometry. NHE V(max) correlated with plasma insulin (r=0.80; P<0.001), but birth weight was unrelated to V(max), K(m) or Hill coefficient for H(i)(+). However, pH(i) correlated with birth weight (r=0.74; P=0.002), insulin sensitivity (r=0.52; P<0.05), fasting glucose (r=-0.52; P<0.05) 2 h insulin (r=0.51; P<0.05) 2 h glucose (r=-0.54; P<0.05). In conclusion, red cell SLC is related to IRS variables, but not with birth weight measures. In contrast, low intracellular pH(i) is related to both low birth weight and adult insulin resistance, suggesting it might be a 'programmed' cell phenotype, although this is not apparently explained by altered NHE kinetics.