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In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance

International Journal of Obesity volume 24, pages 735–741 (2000)Cite this article

Abstract

BACKGROUND: Circulating lymphocytes of obese individuals with and without type 2 diabetes have derangements of pyruvate dehydrogenase (PDH) that are described as reflecting a disorder underlying systemic insulin resistance, namely basal activity below normal and, in vitro, unresponsiveness to insulin at 33 pmol/l and activation at 330 pmol/l instead of activation and inhibition as in controls.

OBJECTIVE: To explore whether the above enzyme derangements are overcome in obese individuals on dexfenfluramine treatment, known to improve poor peripheral insulin sensitivity.

METHODS: Fifteen obese diabetic patients and 15 age-matched euglycaemic obese subjects with normal glucose tolerance were enrolled for a trial composed of two 21-day periods; in the first (D-21–D0), participants received a placebo, and in the second (D0–D21), dexfenfluramine (30 mg/day). At D-21, D0 and D21 participants were evaluated for weight, BMI, fasting glycaemia (FG), fasting insulinaemia (FI), fasting insulin resistance index (FIRI), 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 D2, basal PDH activity and clinical parameters were assayed.

RESULTS: In both groups of participants at D0 all parameters tested were constant with respect to D-21; at D2, only basal PDH activity rose significantly; at D21, basal and insulin stimulated PDH activities were normalized and weight decreased significantly, as did FG, FI, FIRI and G-AUC in the diabetic, and FI, FIRI, G-AUC and I-AUC in the non-diabetic participants.

CONCLUSION: In obese, non-diabetic and diabetic individuals on dexfenfluramine treatment, amelioration of clinical parameters and indexes of poor insulin sensitivity of blood glucose homeostasis are preceded by correction, in their circulating lymphocytes, of PDH derangements described as reflecting a disorder underlying insulin resistance.

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Acknowledgements

The authors are indebted to the Institute des Recherches Internationales Servier, I.R.I.S. (Paris, France) for financial support to the study. The work was in part performed with a financial grant from Ministero dell’ Università e della Ricerca Scientifica e Tecnologica -Italy.

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Authors and Affiliations

  1. Department of Experimental Medicine and Oncology, Section of Biochemistry, University of Turin, Turin, Italy

    M Piccinini, I Rabbone & MT Rinaudo

  2. Department of Internal Medicine, University of Turin, Turin, Italy

    RF Novi & G Alberto

  3. Department of Paediatric Sciences, University of Turin, Turin, Italy

    M Mostert, A Musso & S Vai

  4. Maria Vittoria Hospital, Karen Bruni Antidiabetic Centre, Turin, 10100, Italy

    S Gamba

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  1. M Piccinini
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Correspondence to MT Rinaudo.

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Piccinini, M., Rabbone, I., Novi, R. et al. In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance. Int J Obes 24, 735–741 (2000). https://doi.org/10.1038/sj.ijo.0801212

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