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Acute dexfenfluramine administration normalizes glucose tolerance in rats with insulin‐deficient diabetes
Author(s) -
ARORA R.,
DRYDEN S.,
McKIBBIN P. E.,
WILLIAMS G.
Publication year - 1994
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.1994.tb00986.x
Subject(s) - dexfenfluramine , medicine , diabetes mellitus , endocrinology , insulin , anorectic , dose , streptozotocin , type 2 diabetes , basal (medicine) , fenfluramine , body weight , serotonin , receptor
. Dexfenfluramine has been shown to lower blood glucose concentrations independently of its effects in reducing food intake and body weight, in human and animal syndromes of non‐insulin dependent diabetes. This study aimed to determine whether dexfenfluramine could also reduce glycaemia in rats with severe insulin‐deficient diabetes induced by the β‐cell toxin, streptozotocin (55 mg kg ‐1 ). Three weeks after diabetes induction, nine groups (each n = 10) of diabetic and non‐diabetic rats underwent oral glucose tolerance tests (1 g kg ‐1 , by gavage). These tests were preceded by 12–18 h of fasting to remove the confounding effects of hyperphagia in diabetic rats, and to stabilize glycaemia. Dexfenfluramine (1·0 mg kg ‐1 ), given 2 h before the glucose challenge, significantly reduced basal glycaemia and decreased the post‐challenge glycaemic rise ( P <0·01 vs. untreated diabetics). Dexfenfluramine dosages of 2·5 and 5·0 mg kg ‐1 both further flattened the post‐challenge glycaemic profiles (both P <0·01 vs. untreated diabetics) and achieved levels that did not differ significantly from those in non‐diabetics (both P > 0·05). Subsequently, the studies using dexfenfluramine 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 non‐diabetic values, and were not significantly altered by dexfenfluramine. Acute 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 concentrations were not increased, dexfenfluramine probably acts by enhancing and/or mimicking insulin action. The magnitude of this effect suggests that dexfenfluramine could find application as adjunctive treatment in the management of human insulin‐dependent diabetic patients with insulin insensitivity, such as that associated with obesity.