In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance

BACKGROUND: Circulating lymphocytes of obese individuals with and without t ype 2 diabetes have derangements of pyruvate dehydrogenase (PDH) that are d escribed as reflecting a disorder underlying systemic insulin resistance, n amely basal activity below normal and, in vitro, unresponsiveness to insuli n at 33 pmol/l and activation at 330 pmol/l instead of activation and inhib ition as in controls. OBJECTIVE: To explore whether the above enzyme derangements are overcome in obese individuals on dexfenfluramine treatment, known to improve poor peri pheral insulin sensitivity. METHODS: Fifteen obese diabetic patients and 15 age-matched euglycaemic obe se subjects with normal glucose tolerance were enrolled for a trial compose d of two 21-day periods; in the first (D-(21)-D-0), participants received a placebo, and in the second (D-0- D-21), dexfenfluramine (30 mg/day). At D- (21), D-0 and D-21 participants were evaluated for weight, BMI, fasting gly caemia (FG), fasting insulinaemia (FI), fasting insulin resistance index (F IRI), area under the glycaemic (G-AUC) and insulinaemic (I-AUC) curves from an OGT test, and for PDH activity assayed in their circulating lymphocytes before (basal activity) and after incubation with 33 or 330 pmol/l insulin . At D-2, basal PDH activity and clinical parameters were assayed. RESULTS: In both groups of participants at D-0 all parameters tested were c onstant with respect to D-21; at D-2, only basal PDH activity rose signific antly; at D-21, basal and insulin stimulated PDH activities were normalized and weight decreased significantly, as did FG, Fl, FIRI and G-AUC in the d iabetic, and FI, FIRI, G-AUC and I-AUC in the non-diabetic participants. CONCLUSION: In obese, non-diabetic and diabetic individuals on dexfenfluram ine treatment, amelioration of clinical parameters and indexes of poor insu lin sensitivity of blood glucose homeostasis are preceded by correction, in their circulating lymphocytes, of PDH derangements described as reflecting a disorder underlying insulin resistance.