Improvement of Insulin-Induced Glucose Disposal in Obese Patients With NIDDM After 1-Wk Treatment With <i>d</i>-Fenfluramine

Scheen, André; Paolisso, Giuseppe; Salvatore, Teresa; Lefèbvre, Pierre

doi:10.2337/diacare.14.4.325

Cited by 69 publications

(46 citation statements)

References 24 publications

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“…4 In the participants of this study enzyme response to insulin, in vitro, is impaired before but not at the end of treatment, suggesting this is so also for generation of the intermediates, ie the plasma membrane is the site of an impairment targeted by dexfen¯uramine. In line with this conclusion is that, in improving insulin sensitivity, dexfen¯uramine is believed to target components beyond the insulin receptor 12 and evidence exists that defective metabolic insulin control in obese non-diabetic and diabetic individuals stems from a postreceptor impairment. 29 ± 34 Poor PDH activity and the in vitro alterations are never observed as single defects, ie they always come together.…”

Section: Discussionsupporting

confidence: 50%

“…11 ± 17 However, the mechanism underlying this effect is not clearly understood and is envisaged to involve components beyond the insulin receptor. 12 Here we explore whether in obese individuals with and without type 2 diabetes, dexfen¯uramine ameliorates the above-mentioned PDH derangements. In mammalian tissues PDH is present in mitochondria as a polymeric protein (PDH complex, PDC), in which one of the subunits exists in a balance between a phosphorylated inactive (PDHb) and a dephosphorylated active (PDHa) form, thereby playing the role of a regulatory component.…”

Section: Introductionmentioning

confidence: 99%

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In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance

et al. 2000

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BACKGROUND: Circulating lymphocytes of obese individuals with and without type 2 diabetes have derangements of pyruvate dehydrogenase (PDH) that are described as re¯ecting a disorder underlying systemic insulin resistance, namely basal activity below normal and, in vitro, unresponsiveness to insulin at 33 pmolal and activation at 330 pmolal instead of activation and inhibition as in controls. OBJECTIVE: To explore whether the above enzyme derangements are overcome in obese individuals on dexfenuramine treatment, known to improve poor peripheral insulin sensitivity.

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Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance

et al. 2000

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“…Insulin excess, for example, occurs when sensitivity to insulin is increased or endogenous glucose production is decreased. In different studies in patients with type 2 diabetes mellitus and nondiabetic patients, the use of fluoxetine and the serotonergic anorectic agent fenfluramine increased insulin sensitivity in the short term, thereby increasing the risk on hypoglycaemia [27][28][29][30][31]. We found that the association between hypoglycaemia and the use of antidepressants was most pronounced for antidepressants from cluster 1 and cluster 2 with corresponding binding properties for the serotonin reuptake inhibitor.…”

Section: Hyperglycaemiamentioning

confidence: 97%

The Association between Antidepressant Use and Disturbances in Glucose Homeostasis: Evidence from Spontaneous Reports

et al. 2007

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Objectives Depression is common in patients with diabetes, and the use of antidepressants may impair glycaemic control. We assessed the association between antidepressant use and hyper-and hypoglycaemia. Methods Based on spontaneous reports listed in the World Health Organization (WHO) Adverse Drug Reaction Database, a case-control study was conducted. The study base consisted of all adverse drug reactions (ADRs) ascribed to antidepressants, antipsychotics and benzodiazepines between 1969 and 2005. Cases were defined as reported ADRs classified as hyper-or hypoglycaemia and separated in different study populations. All other reports were considered as controls. Exposure to antidepressants was the primary determinant investigated. Benzodiazepines and antipsychotics were chosen as reference groups. Potential confounding factors, namely, age, gender, use of antidiabetic medication, use of hyper-or hypoglycaemiainducing comedication and reporting year, were determined on the index date. Multivariate logistic regression was used to evaluate the strength of the association, which was expressed as reporting odds ratios (RORs) with 95% confidence intervals (95% CI). Results Overall, the use of antidepressants was associated with hyperglycaemia [ROR 1.52 (95% CI: 1.20-1.93)] and of hypoglycaemia [ROR 1.84 (95% CI: 1.40-2.42)]. The association with hyperglycaemia was most pronounced for antidepressants with affinity for the 5-HT 2c receptor, histamine-1 receptor and norepinephrinic (NE) reuptake transporter. The association with hypoglycaemia was most pronounced for antidepressants with affinity for the serotonin reuptake transporter. Conclusion The results of this study strengthen the findings in individual case reports that the use of antidepressants is associated with disturbances in glucose homeostasis.

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“…Various anti-obesity drugs, including the fenfluramines (now withdrawn) and orlistat (10,11), have produced Ն10% weight loss in 20 -30% of obese type 2 diabetic patients, with concomitant improvements in glycemic control. Sibutramine is a combined reuptake inhibitor of both serotonin (5-hydroxytryptamine) and norepinephrine and acts centrally to enhance satiety (12).…”

mentioning

confidence: 99%

A Randomized Trial of Sibutramine in the Management of Obese Type 2 Diabetic Patients Treated With Metformin

McNulty

Ur²,

Williams³

2003

Diabetes Care

154

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FOR THE MULTICENTER SIBUTRAMINE STUDY GROUPOBJECTIVE -To evaluate the effects of sibutramine (15 and 20 mg/day) on weight, metabolic control, and blood pressure in metformin-treated obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS-A 12-month randomized prospective placebo-controlled double-blind study was performed. It included 21 primary and secondary care centers in England, Canada, France, and Belgium. A total of 195 subjects (44% male) with type 2 diabetes and a BMI Ͼ27 kg/m 2 were studied. Changes were assessed in weight, blood pressure and resting heart rate, HbA 1c , fasting glucose, and lipids.RESULTS -Sibutramine induced significant weight loss (P Ͻ 0.001) with both 15 mg/day (5.5 Ϯ 0.6 kg at 12 months) and 20 mg/day (8.0 Ϯ 0.9 kg), whereas placebo did not (0.2 Ϯ 0.5 kg). Weight loss Ն10% was achieved by 14 and 27% of subjects receiving 15 and 20 mg, respectively, but by none given placebo. Glycemic control improved in parallel with weight loss, and subjects who lost Ն10% weight showed significant decreases in both HbA 1c (1.2 Ϯ 0.4%, P Ͻ 0.0001) and fasting plasma glucose (1.8 mmol/l, P Ͻ 0.001). HDL cholesterol increased slightly with the higher dose, whereas plasma triglycerides fell with both doses, especially in subjects with weight loss of Ն10% (a 29% decrease, P Ͻ 0.01). Treatment was generally well tolerated. Sibutramine treatment raised sitting diastolic blood pressure by Ն5 mmHg in a higher proportion of patients than did placebo (43% with 15 mg/day vs. 25% with placebo, P Ͻ 0.05), but this effect was less evident in subjects who had a weight loss of Ն10% weight. Pulse rate increased significantly more with sibutramine, being Ն10 bpm higher in 42% of treated patients versus 17% with placebo (P Ͻ 0.01).CONCLUSIONS -Sibutramine can be an effective adjunct to metformin treatment in selected obese type 2 diabetic subjects and improves metabolic control in individuals who lose weight. Diabetes Care 26:125-131, 2003O besity exacerbates insulin resistance, hypertension, dyslipidemia, and atherosclerosis, the main cause of death in type 2 diabetes (1-3). It therefore impedes the management of hyperglycemia and its comorbidities in type 2 diabetes and ultimately shortens life expectancy; the risk of premature death increases progressively in subjects with a BMI Ͼ25 kg/m 2 , to 5-fold in men and 10-fold in women with a BMI Ͼ35 kg/m 2 (4,5). Weight loss confers important benefits in obese type 2 diabetic patients. In subjects with a BMI between 30 and 40 kg/m 2 , weight loss of Ն10% often lowers fasting plasma glucose by 1-2 mmol/l and HbA 1c by 1% (6 -8)-effects comparable to those of oral hypoglycemic drugs. Unfortunately, weight loss is harder to achieve and sustain in type 2 diabetic patients than in nondiabetic people (5,7). In the U.K. Prospective Diabetes Study (UKPDS), only 5-10% of obese type 2 diabetic patients remained adequately treated by dietary and lifestyle approaches after 1 year (9).Various anti-obesity drugs, including the fenfluramines (now withdrawn) and orlistat (10,...

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Improvement of Insulin-Induced Glucose Disposal in Obese Patients With NIDDM After 1-Wk Treatment With d-Fenfluramine

Cited by 69 publications

References 24 publications

In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance

In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance

The Association between Antidepressant Use and Disturbances in Glucose Homeostasis: Evidence from Spontaneous Reports

A Randomized Trial of Sibutramine in the Management of Obese Type 2 Diabetic Patients Treated With Metformin

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