Fenfluramine Effects on Insulin Resistance and Lipogenesis in Genetically Obese (ob/ob) Mice

Pasquine, Teresa A.; Thenen, Shirley W.

doi:10.3181/00379727-166-41053

Cited by 5 publications

(3 citation statements)

References 7 publications

(7 reference statements)

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“…In contrast, no effect was seen either with or without insulin in a hind limb perfusion in rats (6). In the intact organism, improved insulin sensitivity was observed after chronic fenfluramine in obese {ob/ob) mice (7). Similarly, fenfluramine improved glycemic control in obese glucose-intolerant humans and in non-insulin-dependent diabetes mellitus (NIDDM) independent of its effects on food intake and body weight (8).…”

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confidence: 99%

Effect of d-Fenfluramine on Basal Glucose Turnover and Fat-Feeding-Induced Insulin Resistance in Rats

et al. 1989

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There is evidence that fenfluramine improves insulin action independently of its anorectic and weight-loss-inducing properties. Chronic d-fenfluramine also reduces hypothalamic noradrenergic tone, which correlates highly with hepatic glucose output. We report that chronic d-fenfluramine (5 mg.kg-1.day-1) ameliorates insulin resistance induced by high-fat feeding. Insulin action was assessed in adult male rats at basal insulin levels and at hyperinsulinemia (approximately 140 mU/L with the euglycemic clamp technique). Hepatic glucose production, peripheral glucose disposal, and individual tissue glucose metabolism were determined from bolus injections of [3H]-2-deoxyglucose and [14C]glucose. Food intake was matched between groups. Basal glucose turnover was reduced 28% (P less than .05) in fat-fed rats receiving d-fenfluramine (fat + fen). The glucose infusion rate to maintain euglycemia was 22.0 +/- 1.1 mg.kg-1.min-1 in the high-carbohydrate-fed rats, 8.2 +/- 1.0 in fat-fed rats, and 15.1 +/- 0.5 in the fat + fen group. Peripheral glucose disposal, reflecting measured skeletal muscle changes, was reduced by fat feeding (from 23.5 +/- 1.0 to 13.8 +/- 0.6 mg.kg-1.min-1) but was improved by d-fenfluramine (16.9 +/- 0.5, P less than .05 vs. fat fed). Impaired suppression of hepatic glucose output by insulin, caused by fat feeding, was totally reversed by d-fenfluramine. Thus, d-fenfluramine counteracted diet-induced insulin resistance, with the predominant effect on the liver. We hypothesize that d-fenfluramine improves insulin action by reducing hypothalamic noradrenergic tone, which in turn reduces the neural drive to hepatic glucose output and improves the hepatic response to insulin.

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Effect of d-Fenfluramine on Basal Glucose Turnover and Fat-Feeding-Induced Insulin Resistance in Rats

et al. 1989

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“…Одним из таких препаратов является п-этила-метил-3-флюорометилфенэтиламина гидрох лорид (минифаж, пондерал), оказывающий сти мулирующее действие на центральную нервную систему [2]. Фенфлюрамин уменьшает запас и синтез моноаминов (5-гидрокситриптамина) в диэнцефальных отделах мозга [8] [7] в экспериментах на крысах подтвердил, что данный эффект препара та осуществляется за счет улучшения чувстви тельности периферических тканей к инсулину, в особенности мышц.…”

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Mechanisms of the effects of fenfluramine on type II diabetes mellitus in combination with obesity

Балаболкин¹,

Новиков²

1996

Probl Endokrinol (Mosk)

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With obesity-related diabetes, it is possible to use biguanides, which have a slight anorectic effect. The presence of side effects in biguanides often complicates their long-term use, especially in elderly patients who have a history of chronic diseases of the lungs, heart, kidneys, and liver. In such cases, it is advisable to prescribe anorectic drugs that simultaneously affect carbohydrate metabolism.One of these drugs is p-ethyl-a-methyl-3-fluoromethylphenethylamine hydrochloride (minifage, ponderal), which has a stimulating effect on the central nervous system. Fenfluramine reduces the supply and synthesis of monoamines (5-hydroxytryptamine) in the diencephalic regions of the brain, due to which there is a decrease in food requirements and a decrease in body weight.A number of researchers have shown that the hypoglycemic effect of the drug occurs due to peripheral action. Fenfluramine affects the extraneuronal oxidation of monoamins and reduces the level of tryptophan in the blood. T. Pssquire in experiments on rats confirmed that this effect of the drug is achieved by improving the sensitivity of peripheral tissues to insulin, especially muscles.Some researchers observed a decrease in plasma fatty acids and cholesterol levels during treatment with ferfluramine.However, the issue of the effect of the drug on the residual secretion of the C-peptide of b-cells of the pancreas during treatment with fenfluramine is not covered in the literature available to us.In our study, 26 patients with obesity (the control group consisted of 18 healthy subjects who had previously impaired glucose tolerance) showed that fenfluramine restores phase I of insulin secretion on the background of an intravenous load with glucagon or glucose, and compensation for diabetes mellitus during treatment fenfluramine is apparently associated not only with a direct stimulating effect on the -cells of the islets of Langerhans but also with its peripheral effect.

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“…It is structurally related to the trifluormethyl molecule fenfluramine. Evidence suggests that fenfluramine improves insulin action, independent of its effects on food intake and body weight, in normoglycemic obese animal models (4,5). It also has been reported that chronic fenfluramine treatment improved glycemic control in obese, glucose-intolerant and NIDDM humans, independent of its anoretic effect (6,7).…”

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Benfluorex Normalizes Hyperglycemia and Reverses Hepatic Insulin Resistance in STZ-Induced Diabetic Rats

1993

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We have examined the effect of chronic (20 days) oral administration of benfluorex (35 mg/kg) in a rat model of NIDDM, induced by injection of STZ 5 days after birth and characterized by frank hyperglycemia, hypoinsulinemia, and hepatic and peripheral insulin resistance. We assessed the following: 1) basal blood glucose and insulin levels, 2) glucose tolerance and glucose-induced insulin release in vivo and in vitro, and 3) basal and insulin-stimulated in vivo glucose production and glucose utilization, using the insulin-clamp technique in conjunction with isotopic measurement of glucose turnover. The in vivo insulin response of several individual tissues also was evaluated under the steady-state conditions of the clamp, using the uptake of the glucose analogue 2-deoxy-D-glucose as a relative index of glucose metabolism. In the benfluorex-treated diabetic rats, postabsorptive basal plasma glucose levels were decreased (8.1 +/- 0.2 mM compared with 10.5 +/- 0.5 mM in the pair-fed untreated diabetic rats and 6.1 +/- 0.2 mM in the benfluorex-treated nondiabetic rats), whereas the basal and glucose-stimulated intravenous glucose tolerance test plasma insulin levels were not improved. Such a lack of improvement in the glucose-induced insulin release after benfluorex treatment was confirmed under in vitro conditions (perfused pancreas). In the pair-fed untreated diabetic rats, the basal glucose production and overall glucose utilization were significantly increased, and during hyperinsulinemia both liver and peripheral tissues revealed insulin resistance. In the benfluorex-treated diabetic rats, the basal glucose production and basal overall glucose utilization were normalized. After hyperinsulinemia, glucose production was normally suppressed, whereas overall glucose utilization was not significantly improved.(ABSTRACT TRUNCATED AT 250 WORDS)

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Fenfluramine Effects on Insulin Resistance and Lipogenesis in Genetically Obese (ob/ob) Mice

Cited by 5 publications

References 7 publications

Effect of d-Fenfluramine on Basal Glucose Turnover and Fat-Feeding-Induced Insulin Resistance in Rats

Effect of d-Fenfluramine on Basal Glucose Turnover and Fat-Feeding-Induced Insulin Resistance in Rats

Mechanisms of the effects of fenfluramine on type II diabetes mellitus in combination with obesity

Benfluorex Normalizes Hyperglycemia and Reverses Hepatic Insulin Resistance in STZ-Induced Diabetic Rats

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