Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men

Fruehwald‐Schultes, Bernd; Oltmanns, Kerstin M.; Toschek, Barbara; Sopke, Stefan; Kern, Werner; Born, Jan; Fehm, Horst L.; Peters, Achim

doi:10.1053/meta.2002.31332

Cited by 62 publications

(40 citation statements)

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“…* Denotes statistical significance (P<0·05). Glueck et al 2001, Fruehwald-Schultes et al 2002; however, in other studies, no effect on serum leptin was found (Guler et al 2000, Mannucci et al 2001, Uehara et al 2001, Ciaraldi et al 2002, Sivitz et al 2003. Possible explanations for these discrepancies may be the length of treatment and the study population, with obese people showing a decrease in leptin levels after long-term treatment.…”

Section: Discussionmentioning

confidence: 82%

Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes

Klein¹,

Westphal²,

Kraus³

et al. 2004

Journal of Endocrinology

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Metformin is an anti-diabetic drug with anorexigenic properties. The precise cellular mechanisms of its action are not entirely understood. Adipose tissue has recently been recognized as an important endocrine organ that is pivotal for the regulation of insulin resistance and energy homeostasis. Due to its thermogenic capacity brown adipose tissue contributes to the regulation of energy metabolism and is an attractive target tissue for pharmacological approaches to treating insulin resistance and obesity. Leptin is the prototypic adipocyte-derived hormone inducing a negative energy balance. We investigated effects of metformin on adipocyte metabolism, signalling, and leptin secretion in a brown adipocyte model. Metformin acutely stimulated p44/p42 mitogenactivated protein (MAP) kinase in a dose-(3·2-fold at 1 mmol/l, P<0·05) as well as time-dependent (3·8-fold at 5 min, P<0·05) manner. This stimulation was highly selective since phosphorylation of intermediates in the stress kinase, janus kinase (JAK)-signal transducer and activator of transcription (STAT), and phosphatidylinositol (PI) 3-kinase signalling pathways such as p38 MAP kinase, STAT3, and Akt was unaltered. Furthermore, chronic metformin treatment for 12 days dose-dependently inhibited leptin secretion by 35% and 75% at 500 µmol/l and 1 mmol/l metformin respectively (P<0·01). This reduction was not caused by alterations in adipocyte differentiation. Moreover, the impairment in leptin secretion by metformin was reversible within 48 h after removal of the drug. Pharmacological inhibition of p44/p42 MAP kinase prevented the metformin-induced negative effect on leptin secretion. Taken together, our data demonstrate direct acute effects of metformin on adipocyte signalling and endocrine function with robust inhibition of leptin secretion. They suggest a selective molecular mechanism that may contribute to the anorexigenic effect of this antidiabetic compound.

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Section: Discussionmentioning

confidence: 82%

Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes

Klein¹,

Westphal²,

Kraus³

et al. 2004

Journal of Endocrinology

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“…Metformin has been reported to have no effect on plasma adiponectin [19,20], to have no effect on or modestly reduce plasma leptin with short-term use [21,22], and to reduce plasma leptin with long-term use [23].…”

Section: Introductionmentioning

confidence: 99%

Metformin increases plasma ghrelin in Type 2 diabetes

Doogue¹,

Begg

Moore³

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Metformin, unlike the other major antihyperglycaemic drugs, is not associated with weight gain.• Ghrelin is an appetite-stimulating hormone whose concentrations vary in relation to food, obesity and diabetes control.• Reports are conflicting about how metformin affects ghrelin concentrations, and this study was aimed at resolving this issue in patients with Type 2 diabetes. WHAT THIS STUDY ADDS• In this study an increase in ghrelin concentrations was seen in response to metformin treatment in patients with Type 2 diabetes. • This effect was opposite to what might be expected if the effect of metformin on weight control was mediated via suppression of ghrelin.• It is likely that the ghrelin response was secondary to improved glycaemic control.• Meal time changes in appetite and satiety did not correlate with changes in ghrelin, which suggests ghrelin may not be important in meal initiation. AIMSMetformin treatment of Type 2 diabetes is not usually associated with weight gain, and may assist with weight reduction. Plasma ghrelin concentrations are inversely associated with obesity and food intake. Metformin might therefore affect ghrelin concentrations, although previous studies have shown variable results in this regard. The primary aim of this study was to determine the effect of metformin on plasma ghrelin, appetite and satiety in patients with Type 2 diabetes. METHODSEighteen patients with Type 2 diabetes were studied before and after 6 weeks of metformin treatment, which was titrated to 1 g b.d. On the study days patients were fed standard meals of 390 kcal at 08.00 and 12.30 h, plasma samples were collected at 15-and 30-min intervals, and appetite and satiety were measured on visual analogue scales. Changes in the area under the concentration-time curves (AUCs) of plasma ghrelin, insulin, glucose, appetite and satiety were assessed and examined for correlations with metformin AUCs. Changes in fasting adiponectin and leptin were also measured. RESULTSTreatment with metformin increased the mean AUC (07.30-16.30 h) of plasma ghrelin by 24% (P = 0.003), while decreasing those of glucose by 19% (P < 0.001) and insulin by 19% (P = 0.001). No changes were detected in hunger and satiety, or in fasting adiponectin or leptin concentrations. There were no clear correlations between metformin plasma concentrations (AUC) and changes in plasma glucose, insulin or ghrelin.

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“…С дру гой сто ро ны, соб ст вен ная весь ма вы со кая кон цен т ра ция ади -по нек ти на в кро ви (до 0,01% от всех бел ков плаз -мы), «мно го про филь ность» вли я ний ади по ци то -ки нов и ряд дру гих при чин де ла ют бо лее оп рав -дан ным, по мне нию не ко то рых ис сле до ва те лей [34,35], фар ма ко те ра пев ти че с кий под ход, на прав -лен ный на из ме не ние эн до ген но го об ра зо ва ния этих со еди не ний и их эф фек тов. При срав не нии в дан ном от но ше нии ан ти ди а бе ти че с ких средств и ин су лин-сен си ти за то ров (ти па ан ти ди а бе ти че с -ких би гу а ни дов и аго ни с тов PPARγ-ти а зо ли дин -ди о нов, ко то рые об ла да ют про ти во опу хо ле вым эф фек том за счет мно го об раз ных ме ха низ мов дей ст вия [4]) трог ли та зон и ро зиг ли та зон сти му -ли ро ва ли про дук цию ади по нек ти на в жи ро вой тка ни, а би гу а нид мет фор мин этой спо соб но с тью не об ла дал [41], но сни жал кон цен т ра цию леп ти -на в кро ви [21]. Боль шой ин те рес пред став ля ют пре па ра ты, яв ля ю щи е ся ин ги би то ра ми ФНО-α (ин флик си маб, эта нер цепт и др.)…”

Section: лм бер ш тейнunclassified

Ozhirenie i onkologicheskie zabolevaniya: staraya problema v novom svete

Bershteyn¹

2006

Obes. metabol.

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Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men

Cited by 62 publications

References 0 publications

Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes

Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes

Metformin increases plasma ghrelin in Type 2 diabetes

Ozhirenie i onkologicheskie zabolevaniya: staraya problema v novom svete

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