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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.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.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 less than 0.001), and that systolic blood pressure (P less than 0.05) and serum HDL cholesterol (P less than 0.05) were higher in the discordant diabetic twins than in their nondiabetic co-twins. Median (95 percent 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 less than 0.005; n = 26); activity levels were not related to either disease duration or blood glucose control.An elevation in Na-Li countertransport activity has been noted in nonnephropathic 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.