On the role of 5-hydroxytryptamine in the peripheral action of fenfluramine: studies with the isolated rat soleus muscle

Sasson, Shlomo; Kunievsky, Baruch; Nathan, C.; Ceras, Erol

doi:10.1016/0006-2952(90)90215-7

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…These observations with benfluorex are in line with those reported with the related compound, fenfluramine, suggesting a failure of the drug to affect in vitro basal and insulin-stimulated glucose transport in rat skeletal muscle (16,17) or a very marginal ability to ameliorate insulin resistance induced by fat feeding in skeletal muscles and white adipose tissues (5,18,19).…”

Section: Discussionsupporting

confidence: 83%

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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Section: Discussionsupporting

confidence: 83%

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

1993

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“…Additionally, we found a shift of glycolytic activity from liver to muscle and, overall, a carbohydrate-and protein-sparing effect of DF [24]. In isolated hepatocytes, insulin-like and glucagon-antagonizing effects of DF were found [25][26][27] while in isolated muscle cells, an insulin-permissive effect was described [28]. Richter et al [29] reported an inhibition of catecholamine-stimulated in vitro lipolysis by DF in human fat cells whereas Al-Sieni et al [30] found a decreased incorporation of glucose into fatty acids but an increased lactate production by pieces of epididymal adipose tissue taken from DF-treated rats.…”

Section: Introductionmentioning

confidence: 61%

In situ Metabolic and Hemodynamic Response to Dexfenfluramine in White Adipose Tissue of Rats

Boschmann

Adams²,

Schimrigk³

2001

Ann Nutr Metab

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Serotonergic neurons are included in the regulation of eating behavior and energy metabolism. Dexfenfluramine (DF), a serotonin releaser and reuptake inhibitor, is known to reduce food intake and body weight and to improve the metabolic profile of obese subjects with and without metabolic complications such as type 2 diabetes. Due to cases of valvular heart diseases, DF was withdrawn from the market in 1997. However, serotonergic drugs are still used in clinical practice. We studied the hemodynamic and metabolic changes induced by in situ perfusion of inguinal subcutaneous adipose tissue (SAT) of normal-weight rats with either 1 µM isoproterenol (IP) or 5 µMDF using the microdialysis technique. Perfusion of SAT with IP resulted in an increase in blood flow (+25%) and lipolysis (+35%) when compared to baseline. In contrast to that, perfusion of SAT with DF resulted in a decrease in blood flow (–25%) and lipolysis (–35%). Additionally, dialysate glucose was decreased and dialysate lactate was increased during perfusion with DF, indicating stimulation of glucose uptake and the glycolytic pathway. It is concluded that DF reduces blood flow and lipolysis whereas it stimulates the glycolytic pathway in SAT and that this could contribute to the positive metabolic outcome, i.e., lowered blood lipids and fat mass of DF-treated obese subjects.

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“…29 ± 31 Although fen¯uramine itself did not signi®cantly after 2-deoxyglucose uptake into the muscle cells, its active metabolite nordexfenuramine increased insulin-stimulated 2-deoxyglucose uptake, presumably via a mechanism that is independent of serotonin. 32 The lack of effect of the anorectic agent phentermine (a noradrenaline and dopamine releaser) 33 on 2-deoxyglucose uptake by the muscle cells substantiates that an improvement of insulin sensitivity is not a general feature of amphetamine-based anorectic agents. 34 Thus, sibutramine acts via its metabolites to increase insulin-sensitive glucose uptake by cultured L6 muscle cells.…”

Section: Discussionmentioning

confidence: 96%

Sibutramine metabolites increase glucose transport by cultured rat muscle cells

et al. 2001

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BACKGROUND:The anti-obesity agent sibutramine, a serotonin and noradrenaline reuptake inhibitor (SNRI), has been shown to reduce insulin resistance and improve glycaemic control in obese-diabetic obaob mice and overweight type 2 diabetic patients. OBJECTIVE: To investigate whether sibutramine or its metabolites act directly on muscle cells to improve glucose uptake and insulin action. DESIGN: Uptake of the non-metabolized glucose analogue 2-deoxyglucose was measured in cultured L6 rat muscle cells after incubation with sibutramine, its two pharmacologically active metabolites and related agents. RESULTS: Sibutramine itself (10 78 ± 10 76 M) did not signi®cantly affect 2-deoxyglucose uptake during incubations up to 72 h. The primary amine metabolite M2 (10 77 and 10 76 M) increased basal and insulin-stimulated 2-deoxyglucose uptake (by 12% and 34%) after 24 h incubation. These effects of M2 were lost by 72 h incubation. However, the secondary amine metabolite M1 (10 76 M) increased basal and insulin-stimulated 2-deoxyglucose uptake (by 50%) after 72 h incubation, although M1 was ineffective after 24 h. M2 stimulated 2-deoxyglucose uptake in the presence of LY-294,002 (an inhibitor of phosphatidylinositol 3-kinase) but the effect of M2 was inhibited by cytochalasin B, which acutely blocks glucose transporters. Incubations with serotoninergic, noradrenergic and dopaminergic agents, or agents known to stimulate release or inhibit reuptake of these substances in nervous tissues indicated that the sibutramine metabolites were not affecting 2-deoxyglucose uptake via mechanisms associated with their SNRI properties. CONCLUSIONS: Sibutramine metabolites can improve insulin-sensitive 2-deoxyglucose uptake by cultured muscle cells independently of SNRI effects.

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On the role of 5-hydroxytryptamine in the peripheral action of fenfluramine: studies with the isolated rat soleus muscle

Cited by 6 publications

References 25 publications

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

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

In situ Metabolic and Hemodynamic Response to Dexfenfluramine in White Adipose Tissue of Rats

Sibutramine metabolites increase glucose transport by cultured rat muscle cells

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