Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disease characterized by progressive weakness and severe muscle wasting. Alterations in carbohydrate metabolism are often associated with neuromuscular disorders. We performed oral glucose tolerance tests and insulin binding studies on erythrocytes from 17 DMD and 8 normal males. Furthermore, we measured insulin binding to erythrocytes from 12 normal males and from 11 mothers and 10 sisters of affected males. As a group, DMD patients had mild glucose intolerance and both fasting and postabsorptive marked hyperinsulinemia (insulin resistance). Levels of glucose and insulin, expressed as incremental areas under their respective curves, were significantly elevated in the wheelchair-ridden patients. Incremental areas of glucose (0-2 h) and insulin (0-5 h) were 42 +/- 5 mg/dl X h (mean +/- SEM) and 96 +/- 18 microU/ml X h, respectively, in normal subjects and 71 +/- 6 (P less than 0.05) and 206 +/- 30 (P less than 0.05), respectively, in the wheelchair-confined DMD patients. All of the ambulatory DMD males had normal oral glucose tolerance tests. Insulin binding to erythrocytes was 20-30% lower (P less than 0.01) in all DMD patients than in normal males appropriately matched for age and degree of sexual development. This difference in binding was a result of lower affinity of the insulin receptor in DMD erythrocytes. On the other hand, insulin binding to fibroblasts was the same in normal males and DMD patients, suggesting that the abnormality of erythrocyte binding in DMD is probably not genetically induced. Insulin binding to erythrocytes and monocytes was the same in all females studied, regardless of whether they were carriers of the DMD gene. Our results suggest that abnormal insulin binding in DMD erythrocytes is an acquired rather than genetic abnormality, but insulin binding is not helpful in the identification of carrier females. The defect in insulin binding in DMD is present before the development of insulin resistance, which occurs only in severely immobilized patients. Thus, the cause of the insulin resistance in DMD may reside at steps beyond the binding of insulin to its receptor.