Increased insulin responsiveness after CS-045 treatment in diabetes associated with Werner's syndrome

Abstract

Werner's syndrome is a rare inheritated disorder characterized by accelerated aging and is often accompanied by diabetes mellitus or impaired glucose tolerance. Previous reports suggest that insulin resistance is involved in the development of diabetes associated with Werner's syndrome. In the present study, CS-045((±)-5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-thiazolidinedione, a new oral hypoglycemic agent which reportedly reduces insulin resistance, was administered to 2 Werner's syndrome patients. The patients were hospitalized for the duration of the study. During a pretreatment period lasting 8 weeks the patients received a controlled diet, however, their previous treatment was unchanged. Throughout the 4-week treatment period, each subject's blood glucose level was measured 7 times each day (07:30, 10:00, 11:30, 14:00, 17:30, 20:00, 22:00) for 1 week at 8, 4, and 1 week before treatment and at 2 and 4 weeks after treatment. To assess insulin action, the euglycemic glucose clamp technique was performed in these subjects at insulin infusion rates of 20, 120 and 400 mU/kg/min before and after 4 weeks of treatment. After 4 weeks of treatment with CS-045, the mean blood glucose level at each time point measured in this study was markedly lower compared to the corresponding pretreatment level. The mean glucose disposal rate, as estimated using the euglycemic glucose clamp technique, was increased from 0.01 ± 0.00, 2.58 ± 0.11 and 5.61 ± 0.37 mg/kg/min to 2.53 ± 0.12, 4.20 ± 0.13 and 9.20 ± 0.13 mg/kg/min in case 1 and from 0.01 ± 0.00, 2.83 ± 0.63, 5.42 ± 0.68 mg/kg/min to 1.59 ± 0.32, 5.70 ± 0.66, and 11.84 ± 0.82 mg/kg/min in case 2 at insulin infusion rates of 20, 120 and 400 mU/kg/min, respectively. The dose-response curves obtained after the treatment were shifted to the left. The present study is the first to report the administration of CS-045 in Werner's syndrome and the results suggest that CS-045 improves glucose tolerance in Werner's syndrome by increasing insulin responsiveness.