ACUTE DEXFENFLURAMINE ADMINISTRATION NORMALIZES GLUCOSE-TOLERANCE IN RATS WITH INSULIN-DEFICIENT DIABETES

Dexfenfluramine has been shown to lower blood glucose concentrations i ndependently of its effects in reducing food intake and body weight, i n human and animal syndromes of non-insulin dependent diabetes. This s tudy aimed to determine whether dexfenfluramine could also reduce glyc aemia in rats with severe insulin-deficient diabetes induced by the be ta-cell toxin, streptozotocin (55 mg kg(-1)). Three weeks after diabet es induction, nine groups (each n = 10) of diabetic and non-diabetic r ats underwent oral glucose tolerance tests (1 g kg(-1), by gavage). Th ese tests were preceded by 12-18 h of fasting to remove the confoundin g effects of hyperphagia in diabetic rats, and to stabilize glycaemia. Dexfenfluramine (1.0 mg kg(-1)), given 2 h before the glucose challen ge, significantly reduced basal glycaemia and decreased the post-chall enge glycaemic rise (P < 0.01 vs. untreated diabetics). Dexfenfluramin e dosages of 2.5 and 5.0 mg kg(-1) both further flattened the post-cha llenge glycaemic profiles (both P < 0.01 vs. untreated diabetics) and achieved levels that did not differ significantly from those in non-di abetics (both P > 0.05). Subsequently, the studies using dexfenflurami ne dosages of 2.5 and 5.0 mg kg(-1) were repeated to determine whether the drug affected plasma insulin levels 2 h after dosing. In diabetic rats, plasma insulin concentrations were reduced to 10-20% of nondiab etic values, and were not significantly altered by dexfenfluramine. Ac ute dexfenfluramine administration therefore improves and (at dosages of 2.5 and 5.0 mg kg(-1)) essentially normalizes glucose tolerance in rats with severe insulin-deficient diabetes. As circulating insulin co ncentrations were not increased, dexfenfluramine probably acts by enha ncing and/or mimicking insulin action. The magnitude of this effect su ggests that dexfenfluramine could find application as adjunctive treat ment in the management of human insulin-dependent diabetic patients wi th insulin insensitivity, such as that associated with obesity.