Benfluorex is a hypolipidaemic agent with biguanide-like properties. To evaluate its blood glucose lowering action, a single-blind study protocol was designed. Two groups of seven type II (non-insulin-dependent) diabetic patients matched for age (50 ± 4 vs. 53 ± 1 years), sex, body mass index (27.8 ± 0.6 vs. 26.5 ± 0.7 kg/m²), and duration of diabetes were studied before and after 1 month of treatment with benfluorex 150 mg tid (= tres in die = three times a day), PO (= per os = by mouth) or a placebo, respectively. All patients had previously been treated by diet alone. In all patients, parameters of glucose and lipid metabolism were obtained. Insulin sensitivity was assessed by means of a euglycaemic (5.1 ± 0.1 mM) hyperinsulinaemic (516 ± 28 pM) clamp performed in combination with [3⁻³H]glucose infusion and indirect calorimetry. In no case was there a significant change in body mass index (27.6 ± 0.5 vs. 26.4 ± 0.7 kg/m²). After 1 month of treatment, fasting plasma glucose (6.8 ± 0.2 vs. 8.1 ± 0.6 mM) and HbA_1C (glycated haemoglobin; 6.5 ± 0.2 vs. 8.0 ± 0.7%) were lower in the benfluorex group than in the placebo-treated patients (both p < 0.05). No change was observed in hepatic glucose production (HGP) (13.5 ± 1.4 vs. 13.9 ± 1.1 μmol/min per kg), the basal rate of glucose, and lipid oxidation and non-oxidative glucose metabolism, or in plasma triglyceride and total cholesterol concentrations. During euglycaemic hyperinsulinaemia, the rate of insulin-mediated glucose disposal was enhanced by benfluorex (34.5 ± 1.1 μmol/min per kg) as compared with the placebo (27.2 ± 4.0 μmol/min per kg; p < 0.05). In both cases, HGP was completely suppressed. Concomitant with the rise in the rate of glucose disposal, glucose oxidation was not affected (12.3 ± 2.0 vs. 12.1 ± 1.0 μmol/min per kg), while the increase in non-oxidative glucose metabolism (22.2 ± 1.9 vs. 14.2 ± 2.0; p < 0.05) accounted for the entire improvement in insulin-mediated glucose metabolism. Both the plasma free fatty acid (FFA) levels and the rate of lipid oxidation were equally suppressed after benfluorex or the placebo. Our results demonstrate that short-term administration of benfluorex to diabetic patients with mild fasting hyperglycaemia induces an amelioration of glucose control even in the absence of a hypolipidaemic effect. The blood glucose lowering action of the drug seems to be associated with a peripheral effect on non-oxidative glucose metabolism.

References

1 De Fronzo RA, Bonadonna RC, and Ferrannini E: Pathogenesis of NIDDM: a balanced overview. Diabetes Care 15: 318–368, 1992.
10.2337/diacare.15.3.318
CAS PubMed Web of Science® Google Scholar
2 De Fronzo RA, and Ferrannini E: Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14: 173–194, 1991.
10.2337/diacare.14.3.173
PubMed Web of Science® Google Scholar
3 Reaven GM: Insulin resistance, hyperinsulinemia, hypertriglyceridemia and hypertension: parallels between human disease and rodent models. Diabetes Care 14: 195–202, 1991.
CAS PubMed Web of Science® Google Scholar
4 Del Prato S, Vigili de Kreutzenberg S, Riccio A, and Tiengo A: Hepatic sensitivity to insulin: effects of sulfonylurea drugs. Am J Med 90 (6A): 29S–36S, 1991.
10.1016/0002-9343(91)90415-T
CAS PubMed Google Scholar
5 Beck-Nielsen H, Hother-Nielsen O, and Pedersen O: Mechanism of action of sulfonylureas with special reference to the extrapancreatic effect: an overview. Diabetic Med 5: 613–620, 1985.
10.1111/j.1464-5491.1988.tb01068.x
Google Scholar
6 Kolterman OG, Gray RS, Shapiro G, Scarlett JA, Griffin J, and Olefsky JM: The acute and chronic effect of sulfonylurea therapy in type II diabetic subjects. Diabetes 33: 364–374, 1984.
CAS Web of Science® Google Scholar
7 Simonson DC, Ferrannini E, Bevilacqua S, Smith D, Barrett E, Carlson R, and De Fronzo RA: Mechanism of improvement in glucose metabolism after chronic glyburide therapy. Diabetes 33: 838–845, 1984.
10.2337/diabetes.33.9.838
CAS PubMed Web of Science® Google Scholar
8 Simonson DC, Del Prato S, Castellino P, Groop L, and De Fronzo RA: Effect of glyburide on glycemic control, insulin requirement and glucose metabolism in insulin-treated diabetic patients. Diabetes 36: 136–146, 1987.
CAS PubMed Web of Science® Google Scholar
9 Riccio A, Del Prato S, Vigili de Kreutzenberg S, and Tiengo A: Glucose and lipid metabolism in non-insulin-dependent diabetes. Effect of metformin. Diabetes Metab 17: 180–184, 1991.
CAS PubMed Web of Science® Google Scholar
10 Rossetti L, De Fronzo RA, Gherzi R, Stein P, Andraghetti G, Falzetti G, Shulman GI, Klein-Robbenhaar E, and Cordera R: Effect of metformin on insulin action in diabetic rats: in vivo and in vitro correlations. Metabolism 39: 425–435, 1990.
10.1016/0026-0495(90)90259-F
CAS PubMed Web of Science® Google Scholar
11 Luft D, Schmulling RM, and Eggstein M: Lactic acidosis in biguanide-treated diabetics. A review of 330 cases. Diabetologia 14: 75–87, 1978.
10.1007/BF01263444
PubMed Web of Science® Google Scholar
12 Di Perri T, and Guerrine M: Etude comparative du benfluorex et du clofibrate dans les hyperlipo-protéinémies de type IIa, IIb, IV. Acta Ther 7: 335–340, 1981.
Google Scholar
13 Jaillard J, and Riveline B: Etude à double insu de l'efficacité à long terme du 780SE dans le diabète chimique de l'obèse. Proves Med 103: 92–98, 1975.
Google Scholar
14 Bertolini S, Cordera R, Balestrieri R, Elicio N, Chiodini G, Montagna G, Martini F, Pistocchi G, Corsi A, Gherzi R, Pesenti F, Bonati S, Saturnino M, and Libianchi S: Etude à long terme de l'efficacité du benfluorex chez 83 patients hyperlipidemiques (type IIB et IV) présentant une glycémie normale, ou une anomalie de la tolérance au glucose, ou un diabète non-insulino-dépendant. Sem Hop Paris 60: 2643–2651, 1984.
Web of Science® Google Scholar
15 De Fronzo RA, Tobin JD, and Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 6: 214–223, 1979.
Google Scholar
16 Del Prato S, Bonadonna RC, Bonora E, et al: Characterization of cellular defects of insulin action in type II (non-insulin-dependent) diabetes mellitus. J Clin Invest 91: 484–494, 1993.
10.1172/JCI116226
CAS PubMed Web of Science® Google Scholar
17 Ferrannini E: The theoretical basis of indirect calorimetry: a review. Metabolism 37: 287–301, 1988.
10.1016/0026-0495(88)90110-2
CAS PubMed Web of Science® Google Scholar
18 Somogyi M: A method for determination of blood filtrates for the determination of sugar. J Biol Chem 86: 655–659, 1939.
Google Scholar
19 Del Prato S, Enzi G, Vigili de Kreutzenberg S, et al.: Insulin regulation of glucose and lipid metabolism in massive obesity. Diabetologia 33: 228–236, 1990.
10.1007/BF00404801
CAS PubMed Web of Science® Google Scholar
20 Ferrannini E, Del Prato S, and De Fronzo RA: Glucose kinetics. Tracer methods. In Methods in Diabetes Research, Vol. II, WL Clarke, J Larner, and SL Pohl, Eds. John Wiley, New York, 1986, pp 108–141.
Google Scholar
21 Giustina A, Rocca L, Romanelli G, Zuccato F, and Giustina G: Effects of benfluorex on glucose tolerance, metabolic control, beta-cell secretion, and peripheral insulin sensitivity to insulin in obese type II diabetic patients on a body weight-maintaining diet. Curr Ther Res 45: 33–42, 1989.
Web of Science® Google Scholar
22 Cavallo-Perin P, Estivi P, Boine L. et al.: Benfluorex and blood glucose control in non-insulin-dependent diabetic patients. J Endocrinol Invest 14: 109–113, 1991.
10.1007/BF03350279
CAS PubMed Web of Science® Google Scholar
23 Bernier JJ: Inhibition de la lipase pancréatique par le 780 SE. Nouv Presse Med 4: 974, 1975.
CAS PubMed Web of Science® Google Scholar
24 Duhalut J, Boulanger M, Berigi L, Sicot N, and Bouvier F: 780 SE, a new type of hypolipemic agent: comparative assays in rats. Atherosclerosis 23: 63–72, 1976.
10.1016/0021-9150(76)90118-0
PubMed Web of Science® Google Scholar
25 Ailhaud G, Verrando P, and Negrel R: Long-term effects of benfluorex on glucose utilization in the preadipocyte ob 17 cell line. Diabetologia 21: 241 (Abstract), 1981.
Web of Science® Google Scholar
26 Geleen MJH: Mechanisms responsible for inhibitory effects of benfluorex on hepatic intermediary metabolism. Biochem Pharmacol 32: 1765–1770, 1983.
10.1016/0006-2952(83)90123-5
PubMed Web of Science® Google Scholar
27 De Fronzo RA, Ferrannini E, and Simonson DC: Fasting hyperglycaemia in non-insulin-dependent diabetes mellitus: contribution of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38: 387–395, 1989.
10.1016/0026-0495(89)90129-7
PubMed Web of Science® Google Scholar
28 Consoli A, Nurjhan N, Capani F, and Gerich J: Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 38: 550–557, 1989.
PubMed Web of Science® Google Scholar
29 Hother-Nielsen O, and Beck-Nielsen H: On the determination of basal glucose production rate in patients with type II (non-insulin-dependent) diabetes mellitus using primed-continuous 3-³H-glucose infusion. Diabetologia 33: 603–610, 1990.
10.1007/BF00400204
PubMed Web of Science® Google Scholar
30 Del Prato S, Ferrannini E, and De Fronzo RA: Evaluation of insulin sensitivity in man. In Methods in Diabetes Research, Vol. II, WL Clarke, J Larner, SL Pohl, Eds. John Wiley, New York, 1986, pp 35–76.
Google Scholar
31 Ward WK, Bolgiano DC, McKnight B, Halter JB, and Porte D Jr.: Diminished β-cell secretory capacity in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 74: 1318–1328, 1984.
10.1172/JCI111542
CAS PubMed Google Scholar
32 Eriksson J, Franssila-Kallunki A, Ekstrand A, SaPoranta C, Widen E, Schalin C, and Groop L: Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 321: 337–343, 1989.
10.1056/NEJM198908103210601
CAS PubMed Web of Science® Google Scholar
33 Golay A, Felber JP, Jéquier E, De Fronzo RA, and Ferrannini E: Oxidative and non-oxidative glucose metabolism in non-obese type II (non-insulin-dependent) diabetic patients. Diabetologia 31: 585–591, 1988.
10.1007/BF00264764
CAS PubMed Web of Science® Google Scholar
34 Sommariva D, Tirrito M, Bonfiglioli D, Pogliaghi I, Palumbo P, Raggi U, Branchi C, Ottomano C, and Libianchi S: Effects of benfluorex on serum lipoproteins in diabetic and non-diabetic hypertriglyceridemic patients. Curr Ther Res 39: 281–287, 1986.
Web of Science® Google Scholar
35 Duhault J, Doumith A, Rolland J, and Boulanger M: Comparative effects of benfluorex and phenphormin on in vivo lactic acid production by dog muscle. IRCS Med Sci 12: 835–839, 1984.
Web of Science® Google Scholar
36 Reaven GM: Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes 37: 1595–1607, 1988.
10.2337/diab.37.12.1595
CAS PubMed Web of Science® Google Scholar

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Volume9, IssueS1

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November 1993

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Mechanism(s) of the blood glucose lowering action of benfluorex

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Mechanism(s) of the blood glucose lowering action of benfluorex

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