Na/Li countertransport abnormalities in type 1 diabetes with and without nephropathy are familial

OBJECTIVE - To determine whether there is a familial abnormality in erythro cyte Na/Li countertransport (CT) kinetics in the approximate one-third of t ype 1 diabetic patients that succumb to a familial predisposition to nephro pathy. RESEARCH DESIGN AND METHODS - Erythrocyte Na/Li CT kinetics were measured i n nondiabetic first-degree relatives of type 1 diabetic patients with nephr opathy (DNrel) (n = 32) or without nephropathy (DCrel) (n = 22) and normal control subjects ( n = 25). RESULTS - increases in outside-site Na ion association rate constant and tu rnover rate of Na/Li countertransport (CT) in DNrels caused increases in V- max/K-m and V-max, respectively. Thiol alkylation with N-ethylmaleimide (NE M) modifies these kinetic parameters abnormally in nephropathy. With Na ion s at the outside site of the transporter, thiol alkylation causes a large d ecrease in V-max; but in their absence, V-max, is decreased in normal contr ol subjects, unchanged in DCrels, or increased in DNrels. The relationship between V-max values after thiol alkylation with or without Na ions was dif ferent in DNrels (P < 0.001). Kinetic parameters with and without thiol alk ylation identified 60% of DNrels and 20% of DCrels as abnormal. The single- flux rate assay of Na/Li CT did not give this discrimination, and its use m ay cause discrepancy between studies. CONCLUSIONS - Clinically normal untreated DNrels have the same abnormality in Na/Li CT as the affected patients. DNrels had a metabolic syndrome with increased BMI and plasma triglycerides, bur no elevation in blood pressure. Na/Li CT can detect those type 1 diabetic patients at risk of nephropathy who have a familial abnormality in a membrane thiol protein.