Insulin-dependent diabetic sibling pairs are concordant for sodium-hydrogen antiport activity

Background. Recent findings of enhanced Na+/H+ antiport activity in culture d fibroblasts and immortalized lymphoblasts from type 1 diabetic patients w ith nephropathy support the view that a phenotypic or genotypic factor(s) u nderlies nephropathy risk. This study evaluated the kinetic properties of N a+/H+ antiporter in cultured fibroblasts from families with two siblings af fected by type 1 (insulin-dependent) diabetes. Methods. Seventeen diabetic sibling pairs were studied. The age was 38 +/- 10 years (mean +/- so) in probands, the first to develop diabetes, and 39 /- 7 in siblings; the duration of diabetes was, by definition, longer in pr obands (24 +/- 12 vs. 17 +/- 8 years in siblings). Na+/H+ antiport activity was determined using a microfluorometric technique with the pH sensitive d ye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein skin fibroblasts cultu red for at least six passages. Results. There were no significant differences between probands and sibling s for the following parameters: glycated hemoglobin, 8.3 +/- 0.8% in proban ds and 8.6 +/- 1.4% in siblings; creatinine clearance, 103 +/- 24 ml/min/1. 73 m(2) in probands and 103 +/- 25 in siblings; albumin excretion rate, 6.8 (1 to 860) mu g/min (median and range) in probands and 4.9 (2 to 1334) in siblings. Intracellular pH and buffering capacity were superimposable in th e sibling pairs. The V-max for the antiport was 39.2 +/- 14.7 mmol/liter ce ll/min in probands and 40.3 +/- 17.6 in siblings. The internal pH for half- maximal activation (Km) and Hill coefficient was also similar in probands a nd siblings. There were correlations between probands and siblings in value s for intracellular pH (r = 0.51, P < 0.04), V-max (r = 0.84, P < 0.0001), and buffering capacity (r = 0.53, P < 0.03). Glycated hemoglobin values ove r five years were not significantly correlated in the sibling pairs (r = 0. 3, P > 0.1). V-max was related with the albumin excretion rate (r = +0.49, P = 0.005) and glycated hemoglobin (r = +0.41, P = 0.017) in the total coho rt of sibling pairs. However, multiple regression analysis, using V-max as the dependent variable, found no correlations between any of the subjects' clinical and demographic variables. Conclusions. Familial concordance for Na+/H+ antiport activity in long-term cultured skin fibroblasts from type 1 diabetic siblings suggests that at l east some of the in vitro phenotypical characteristics of these cells are l ikely to be genetically determined and to be, at least in part, independent of in vivo metabolic control.