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Cited by 39GDF15 and Related BiomarkersRegulation of Appetite and ObesityPharmacology and Obesity Treatment

GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin

Open access
Ouyang, Jing, Isnard, Stéphane, Lin, John, Fombuena, Brandon, Peng, Xiaorong, Chen, Yaokai, Routy, Jean-Pierre·2020·Frontiers in Endocrinology
DOI 10.3389/fendo.2020.581839PMC PMC7708317
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Abstract

Weight gain and obesity are global health concerns contributing to morbidity with increased risks of cardiovascular disease, diabetes, liver steatohepatitis and cancer. Pharmacological therapies or bariatric surgery are often required for those who fail to adhere to diet and lifestyle modifications. Metformin, a widely used antidiabetic agent, seems to have a health benefit beyond its anti-hyperglycemic properties, with few side effects. Emerging evidence shows weight loss to be associated with metformin in both diabetic and non-diabetic individuals. Recently, the growth differentiation factor 15 (GDF-15), a member of the transforming growth factor beta superfamily, has been identified as a key mediator of metformin-induced weight loss. Metformin increases the secretion of GDF-15, which binds exclusively to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL). This gut-brain cytokine works as a prominent player in reducing food intake and body weight in health and disease, like anorexia nervosa and cancer. Herein, we critically review advances in the understanding of the weight-reducing effects of metformin via the GDF-15 pathway.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that metformin increases GDF-15 via ATF4/CHOP, and that GDF-15 binding to brainstem GFRAL/RET reduces food intake and body weight in diabetic and non-diabetic people. It synthesizes animal, cellular, and clinical evidence but concludes that GDF-15’s role as a biomarker and its clinical implications require confirmation in large RCTs.

Key findings

  • Metformin is associated with weight loss across populations: in a 4,360-patient DM2 RCT, metformin users lost a mean of 2.9 kg over 5 years, whereas rosiglitazone and glyburide caused gains of 4.8 kg and 1.6 kg; metformin also reduced weight/waist versus placebo in the Diabetes Prevention Program, decreased body weight more than DPP-4 inhibitors in a meta-analysis, and reduced weight in non-diabetic obese women, children, antipsychotic-treated patients, PCOS women, and non-diabetic people living with HIV.
  • Metformin raises GDF-15 in humans: among 8,401 participants with dysglycemia (2,317 on metformin), GDF-15 was linked to metformin dose-dependently, with “1 per mg of metformin treatment led to 8.7 pg/ml of GDF-15 increased in plasma”; Natali et al. found a 40% rise in GDF-15 with metformin (644 vs 299 non-metformin); Coll et al. reported about a 2.5-fold increase after 2 weeks in 9 overweight participants and significantly increased GDF-15 at 6, 12, and 18 months in 86 metformin vs 85 placebo participants; Isnard et al. found increased GDF-15 at 12 weeks on 850 mg twice daily, returning to baseline 12 weeks after discontinuation.
  • Mechanistic evidence: metformin induces integrated stress response regulators ATF4 and CHOP, stimulating GDF-15 secretion; GDF-15 binds exclusively to GFRAL and coreceptor RET in the brainstem, activating nucleus of the solitary tract, hypothalamus, and central amygdala to reduce food intake and appetite. In GDF-15 knockout mice, metformin retained glucose- and insulin-lowering effects but did not induce weight loss; Gfral knockout mice are resistant to GDF-15-induced body weight and food-intake suppression.
  • Cellular/animal GDF-15 induction: 1 mM metformin increased GDF-15 gene expression 25.61-fold in MDA-MB-468 breast cancer cells; 10–100 mM metformin increased GDF-15 in mesenchymal stem cells dose-dependently up to 2-fold control at 100 mM; 600 mg/kg metformin produced a six-fold increase in serum GDF-15 at 4 h and 8 h in obese mice.

Methods

  • Design: critical/narrative review of advances in understanding metformin’s weight-reducing effects via the GDF-15 pathway.
  • Data: literature search using keywords “GDF-15”, “metformin”, “weight”, “diabetes drugs” alone or in combination in PubMed, Google Scholar, and ClinicalTrials.gov; because the relationship between GDF-15 and anti-diabetic drugs is new, all English publications were discussed.
  • Analysis: narrative synthesis of animal, cellular, and clinical studies, summarized in Table 1 with models, sample numbers, metformin doses, and GDF-15 changes; no meta-analysis or formal systematic review process is described.

Limitations

  • Stated by the authors: the mechanism responsible for metformin-induced GDF-15 expression is not yet deciphered; the clinical implication of metformin-induced GDF-15 increase must be assessed in future RCTs; more evidence is needed to verify GDF-15 as a biomarker of metformin’s weight-reducing effects; future studies should define metformin dose and duration and confirm GDF-15 as a biomarker in large RCTs.
  • Evident from the text: this is a narrative review with a non-systematic search and no formal quality assessment; the evidence base is heterogeneous, including animal studies with small groups (e.g., n = 6–7 per group), cellular studies, and clinical studies with small samples (e.g., n = 9 crossover), and some metformin doses are “not mentioned,” limiting causal and generalizability claims.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fendo.2020.581839

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 112 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    GDF-15 mediates the beneficial effects of metformin on energy balance and weight loss independently of insulin pathways.

    “These findings suggest that GDF-15 mediates the beneficial effects of metformin on energy balance and weight loss, independently of insulin pathways.”
    Quote in the paperSubstantial claim
  • Premisecitation

    1 mM metformin upregulates GDF-15 gene expression in breast cancer cells to 26-fold compared with control.

    “In vitro, 1mM of metformin upregulated GDF-15 gene expression in breast cancer cells to 26-fold compared with control (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Williams, 2013, Metformin induces a senescence-associated gene signature in breast cancer cells, J Health Care Poor Underserved source

      Not checked in the free run.

  • Interpretationcitation

    GDF-15 is a key mediator of metformin-induced weight loss.

    “Recently, the growth differentiation factor 15 (GDF-15), a member of the transforming growth factor beta superfamily, has been identified as a key mediator of metformin-induced weight loss.”
    • Also stated in: § Introduction · boosted
      “Studies have shown converging evidence that growth differentiation factor 15 (GDF-15) mediates metformin’s effect on the gut-nervous system axis to decrease body weight (23–26).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [23] Coll, 2020, GDF15 mediates the effects of metformin on body weight and energy balance, Nature source

      Not checked in the free run.

    • cites [24] Day, 2019, Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss, Nat Metab source

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    • cites [25] Isnard, 2020, Repurposing metformin in non-diabetic people living with HIV: Influence on weight and gut microbiota, Open Forum Infect Dis source

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    • cites [26] Yang, 2017, GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand, Nat Med source

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  • Premisecitation

    Metformin and phenformin induce GDF-15 expression in murine and human hepatocytes.

    “Metformin and other biguanides such as phenformin were shown to induce GDF-15 expression in murine and human hepatocytes (23), while the direct effect of other anti-diabetes drugs has not been studied yet.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Coll, 2020, GDF15 mediates the effects of metformin on body weight and energy balance, Nature source

      Not checked in the free run.

  • Interpretationcitation

    There is a direct cause-effect relationship between GDF-15 plasma level change and weight change during and after metformin discontinuation.

    “We showed that metformin, independent of its glucose-lowering effect, increased plasma levels of GDF-15 and decreased weight, and its effects vanished upon discontinuation, establishing a direct cause-effect relationship between GDF-15 plasma level change and weight change during and after metformin discontinuation (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Isnard, 2020, Repurposing metformin in non-diabetic people living with HIV: Influence on weight and gut microbiota, Open Forum Infect Dis source

      Not checked in the free run.

  • May combine two claims. 27
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingcitation

    In non-diabetic, non-obese people living with HIV receiving effective antiretroviral therapy, metformin increased plasma GDF-15 and decreased weight independent of its glucose-lowering effect.

    “We showed that metformin, independent of its glucose-lowering effect, increased plasma levels of GDF-15 and decreased weight, and its effects vanished upon discontinuation, establishing a direct cause-effect relationship between GDF-15 plasma level change and weight change during and after metformin discontinuation (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Isnard, 2020, Repurposing metformin in non-diabetic people living with HIV: Influence on weight and gut microbiota, Open Forum Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The effects of metformin on plasma GDF-15 and weight vanished upon discontinuation.

    “We showed that metformin, independent of its glucose-lowering effect, increased plasma levels of GDF-15 and decreased weight, and its effects vanished upon discontinuation, establishing a direct cause-effect relationship between GDF-15 plasma level change and weight change during and after metformin discontinuation (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Isnard, 2020, Repurposing metformin in non-diabetic people living with HIV: Influence on weight and gut microbiota, Open Forum Infect Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin induces GDF-15 gene expression and elevates circulating GDF-15 in animal and human models.

    “Converging findings showed that metformin induced gdf-15 gene expression and elevated the circulating GDF-15 level in animal and human models ( Table 1 ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GDF-15 reduces food intake and body weight.

    “This gut-brain cytokine works as a prominent player in reducing food intake and body weight in health and disease, like anorexia nervosa and cancer.”
    • Also stated in: § GDF-15 and Weight Loss: Evidencesand Mechanism · plain
      “In addition, elevated GDF-15 expression and circulating levels correlate with further weight loss, reduce food intake and appetite (42, 43, 106).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Lerner, 2016, Growth differentiating factor-15 (GDF-15): A potential biomarker and therapeutic target for cancer-associated weight loss, Oncol Lett source

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    • cites [43] Lerner, 2015, Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients, J cachexia sarcopenia Muscle source

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    • cites [106] Semba, 2020, Elevated Plasma Growth and Differentiation Factor 15 Is Associated With Slower Gait Speed and Lower Physical Performance in Healthy Community-Dwelling Adults, J Gerontol Ser A Biol Sci Med Sci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Metformin increases GDF-15 gene expression and stimulates GDF-15 secretion by direct induction of integrated stress response regulators ATF4 and CHOP.

    “Therefore, current evidence indicates that metformin increases GDF-15 gene expression and stimulate GDF-15 secretion by direct induction of integrated stress response regulators ATF4 and CHOP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    GDF-15 knockout mice weigh more and have increased adiposity associated with increased food intake.

    “Tsai et al. (107) reported that GDF-15 gene knockout mice (Gdf-15 (-/-)) weighed more and had increased adiposity, which was associated with increased food intake, and that infusion of human recombinant GDF-15 was sufficient to raise serum levels in Gdf-15 (-/-) mice to within the normal human range, reducing body weight and food intake.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Tsai, 2013, TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gerstein et al. found GDF-15 linked to metformin treatment in a dose-dependent manner, with 1 mg of metformin treatment leading to 8.7 pg/ml increase in plasma GDF-15.

    “In vivo, Gerstein et al. assayed 237 biomarkers in baseline serum from 8,401 participants with dysglycemia of whom 2,317 received metformin and found that GDF-15 was linked to metformin treatment, in a dose dependent manner (1 per mg of metformin treatment led to 8.7 pg/ml of GDF-15 increased in plasma).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Elevated GDF-15 expression and circulating levels correlate with further weight loss and reduced food intake and appetite.

    “In addition, elevated GDF-15 expression and circulating levels correlate with further weight loss, reduce food intake and appetite (42, 43, 106).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Lerner, 2016, Growth differentiating factor-15 (GDF-15): A potential biomarker and therapeutic target for cancer-associated weight loss, Oncol Lett source

      Not checked in the free run.

    • cites [43] Lerner, 2015, Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients, J cachexia sarcopenia Muscle source

      Not checked in the free run.

    • cites [106] Semba, 2020, Elevated Plasma Growth and Differentiation Factor 15 Is Associated With Slower Gait Speed and Lower Physical Performance in Healthy Community-Dwelling Adults, J Gerontol Ser A Biol Sci Med Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Coll et al. reported in two independent RCTs that metformin reduced food intake and lowered body weight in association with increasing GDF-15 levels.

    “Moreover, Coll et al. (23) reported in two independent RCT that metformin reduced food intake and lowered body weight in association with increasing levels of GDF-15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Coll, 2020, GDF15 mediates the effects of metformin on body weight and energy balance, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin increases GDF-15 secretion and circulating GDF-15 levels.

    “Metformin increases the secretion of GDF-15, which binds exclusively to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL).”
    • Also stated in: § Metformin Induces GDF-15 Via ATF4 and CHOP · boosted
      “Converging findings showed that metformin induced gdf-15 gene expression and elevated the circulating GDF-15 level in animal and human models ( Table 1 ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis showed metformin decreased BMI and waist-to-hip ratio in 11 and 7 RCTs of PCOS women, respectively, compared to placebo.

    “However, a meta-analysis showed that metformin contributed to a decrease of body mass index (BMI) and waist to hip ratio (WHR) in 11 and 7 RCTs of PCOS women respectively, compared to placebo (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Patel, 2017, Effect of metformin on clinical, metabolic and endocrine outcomes in women with polycystic ovary syndrome: a meta-analysis of randomized controlled trials, Curr Med Res Opin source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss.

    “Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metformin was recommended for obesity management in patients with evidence of prediabetes or insulin intolerance by AACE/ACE guidelines.

    “Due to the effects of weight loss, metformin was recommended for obesity management in patients with evidence of prediabetes or insulin intolerance by AACE/ACE guidelines (53).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Garvey, 2016, American Association Of Clinical Endocrinologists And American College Of Endocrinology Comprehensive Clinical Practice Guidelines For Medical Care Of Patients With Obesity, Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinologists source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin induced significant weight loss compared with placebo in non-diabetic obese women, and this effect was associated with gut microbiota alteration.

    “Ejtahed et al. (20) demonstrated in a RCT that metformin induced significant weight loss compared with placebo, and this effect was associated with gut microbiota alteration in non-diabetic obese women.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Ejtahed, 2018, Metformin induces weight loss associated with gut microbiota alteration in non-diabetic obese women: a randomized double-blind clinical trial, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a large RCT involving 4360 DM2 patients, participants lost a mean of 2.9 kg with metformin over 5 years, while rosiglitazone and glyburide induced weight gains of 4.8 and 1.6 kg, respectively.

    “Kahn et al. (49) reported in a large randomized clinical trial (RCT) involving 4360 DM2 patients that participants lost a mean of 2.9 kg with metformin over a period of 5 years, while rosiglitazone and glyburide both induced weight gains of 4.8 and 1.6 kg, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Kahn, 2006, Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, N Engl J Med source

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  • May combine two claims.

    Premisecitation

    GDF-15 forms a complex with GFRAL and RET on the cell surface, then triggers intracellular signaling through the ERK pathway.

    “GDF-15 forms a complex with GFRAL and RET on the cell surface, then triggers an intracellular signaling cascade through the extracellular signal-related kinase (ERK) pathway (40, 113).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Hsu, 2017, Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15, Nature source

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    • cites [113] Asai, 1996, A mutation at tyrosine 1062 in MEN2A-Ret and MEN2B-Ret impairs their transforming activity and association with shc adaptor proteins, J Biol Chem source

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  • May combine two claims.

    Premisecitation

    GFRAL expression is limited to the brainstem and Gfral mRNA is highly expressed in the area postrema of mouse, rat, monkey and human.

    “Unlike Gdf-15 which is expressed in diverse tissues, including kidney, liver, gut, muscle, adipose, and placenta, GFRAL expression is limited to the brainstem and Gfral mRNA is highly expressed in the area postrema of mouse, rat, monkey and human (39–41).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Emmerson, 2017, The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL, Nat Med source

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    • cites [40] Hsu, 2017, Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15, Nature source

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    • cites [41] Mullican, 2017, GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates, Nat Med source

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  • May combine two claims.

    Premisecitation

    The magnitude of weight loss during the 2-year double-blind period was directly related to drug adherence, indicating a potential dose-effect.

    “The magnitude of weight loss during the 2-year double-blind period was directly related to drug adherence, indicating a potential dose-effect (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] 2012, Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infusion of human recombinant GDF-15 into Gdf-15(-/-) mice raises serum levels to within the normal human range and reduces body weight and food intake.

    “Tsai et al. (107) reported that GDF-15 gene knockout mice (Gdf-15 (-/-)) weighed more and had increased adiposity, which was associated with increased food intake, and that infusion of human recombinant GDF-15 was sufficient to raise serum levels in Gdf-15 (-/-) mice to within the normal human range, reducing body weight and food intake.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Tsai, 2013, TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpressing GDF-15 decreases body weight, fat mass and food intake, and improves glucose tolerance in mouse models.

    “On the contrary, overexpressing GDF-15 led to decreased body weight, fat mass and food intake, improving the glucose tolerance in mouse models (83, 108–110).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [83] Chrysovergis, 2014, NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism, Int J Obes (Lond) source

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    • cites [108] Johnen, 2007, Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1, Nat Med source

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    • cites [109] Baek, 2006, Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia, Gastroenterology source

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    • cites [110] Macia, 2012, Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets, PloS One source

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  • May combine two claims.

    Interpretationnone given

    Metformin induces ATF4 and CHOP, which stimulates secretion of circulating GDF-15, which then binds to GFRAL and RET in the brainstem.

    “Metformin induces the expression of integrated stress response regulators ATF4 and CHOP, which stimulates the secretion of circulating GDF-15, which then binds to its exclusive receptor GFRAL and coreceptor RET in the brainstem.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Metformin has additional benefit for conditions like polycystic ovary syndrome, atherosclerosis, cancer, COVID-19, and obesity.

    “Aside from its anti-hyperglycemic effects, metformin has an additional benefit for conditions like polycystic ovary syndrome, atherosclerosis, cancer, coronavirus disease 2019 (COVID-19), and obesity (7–14).”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [7] Pollak, 2017, The effects of metformin on gut microbiota and the immune system as research frontiers, Diabetologia source

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    • cites [8] Kim, 2012, Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells, Biochem Biophys Res Commun source

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    • cites [9] Hirsch, 2013, Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth, Proc Natl Acad Sci U.S.A. source

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    • cites [10] Li, 2009, Metformin inhibits nuclear factor kappaB activation and decreases serum high-sensitivity C-reactive protein level in experimental atherogenesis of rabbits, Heart Vessels source

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    • cites [11] Victor, 2015, Metformin modulates human leukocyte/endothelial cell interactions and proinflammatory cytokines in polycystic ovary syndrome patients, Atherosclerosis source

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    • cites [12] Arrieta, 2019, Effect of Metformin Plus Tyrosine Kinase Inhibitors Compared With Tyrosine Kinase Inhibitors Alone in Patients With Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: A Phase 2 Randomized Clinical Trial, JAMA Oncol source

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    • cites [13] Luo, 2020, Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis, Am J Trop Med Hyg source

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    • cites [14] El-Arabey, 2020, Metformin and COVID-19: A novel deal of an old drug, J Med Virol source

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  • May combine two claims.

    Interpretationcitation

    GDF-15 may induce an aversive response to nutritional stimulation and may be associated with nausea in pregnancy.

    “Moreover, pharmacological recombinant human GDF-15 administration to mice can trigger conditioned-taste aversion, suggesting that GDF-15 may induce an aversive response to nutritional stimulation and may be associated with nausea in pregnancy (102).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Patel, 2019, GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans, Cell Metab source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metformin is widely used as a first-line treatment for type 2 diabetes mellitus owing to its excellent tolerability, safety profile, and lack of hypoglycemic effect.

    “Isolated from French lilac in 1920s, metformin (dimethylbiguanide) has been widely used as a first-line treatment for type 2 diabetes mellitus (DM2), owing to its excellent tolerability, safety profile, and lack of hypoglycemic effect (3–6).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [3] 2019, Standards of Medical Care in Diabetes-2019 Abridged for Primary Care Providers, Clin Diabetes Publ Am Diabetes Assoc source

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    • cites [4] Yale, 2018, Hypoglycemia, Can J Diabetes source

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    • cites [5] Harper, 2013, Pharmacologic management of type 2 diabetes, Can J Diabetes source

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    • cites [6] Bonadonna, 2019, Hypoglycaemia as a function of HbA1c in type 2 diabetes: Insulin glargine 300 U/mL in a patient-level pooled analysis of EDITION 1, 2 and 3, Diabetes Obes Metab source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GDF-15 is a stress-induced protein produced by a variety of cells under stress conditions including tissue injury, anoxia, and inflammation.

    “GDF-15 is a stress-induced protein, produced by a variety of cells under stress conditions including tissue injury, anoxia, and inflammation (28).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Adela, 2015, GDF-15 as a Target and Biomarker for Diabetes and Cardiovascular Diseases: A Translational Prospective, J Diabetes Res source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most DM2 patients are overweight or obese.

    “Dysglycemia is strongly associated with the development of overweight status or obesity, as most DM2 patients are overweight or obese (44–46).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [44] Golay, 2005, Link between obesity and type 2 diabetes. Best practice & research, Clin Endocrinol Metab source

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    • cites [45] 2000, The Diabetes Prevention Program: baseline characteristics of the randomized cohort. The Diabetes Prevention Program Research Group, Diabetes Care source

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    • cites [46] Daousi, 2006, Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors, Postgraduate Med J source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Metformin was reported to extend lifespan in some animal models, acting as a diet mimetic agent.

    “Metformin was also reported to extend lifespan in some animal models, acting as a diet mimetic agent (15–17).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Onken, 2010, Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1, PloS One source

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    • cites [16] Martin-Montalvo, 2013, Metformin improves healthspan and lifespan in mice, Nat Commun source

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    • cites [17] Pryor, 2019, Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy, Cell source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    High GDF15 levels are independently associated with a higher rate of COPD exacerbations and impaired respiratory function.

    “Husebø et al. reported that high levels of GDF15 were independently associated with a higher rate of COPD exacerbations, and impaired respiratory function (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Husebø, 2017, Growth differentiation factor-15 is a predictor of important disease outcomes in patients with COPD, Eur Respir J source

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  • May combine two claims.

    Premisenone given

    Metformin seems to have a health benefit beyond its anti-hyperglycemic properties, with few side effects.

    “Metformin, a widely used antidiabetic agent, seems to have a health benefit beyond its anti-hyperglycemic properties, with few side effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Metformin's effect on weight in women with PCOS is not as well defined and depends on the population and study design.

    “Metformin’s effect on weight in women with PCOS is not as well defined, depending on the population and study design (69–74).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [69] Javed, 2020, The effects of empagliflozin versus metformin on endothelial microparticles in overweight/obese women with polycystic ovary syndrome, Endocr Connect source

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    • cites [70] Preiss, 2008, The effects of 8 months of metformin on circulating GGT and ALT levels in obese women with polycystic ovarian syndrome, Int J Clin Pract source

      Not checked in the free run.

    • cites [71] Jensterle, 2016, Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of liraglutide in obese polycystic ovary syndrome: Randomized control study, Exp Ther Med source

      Not checked in the free run.

    • cites [72] Jensterle Sever, 2014, Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin, Eur J Endocrinol source

      Not checked in the free run.

    • cites [73] Al-Nozha, 2013, Body weight reduction and metformin: Roles in polycystic ovary syndrome, Pathophysiology source

      Not checked in the free run.

    • cites [74] Aghahosseini, 2010, Metformin 2,500 mg/day in the treatment of obese women with polycystic ovary syndrome and its effect on weight, hormones, and lipid profile, Arch Gynecol Obstet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bodyweight is maintained through central nervous system circuitry integrating peripheral metabolic feedback signals of energy surplus or deficit.

    “Bodyweight is usually maintained through central nervous system (CNS) circuitry integrating peripheral metabolic feedback signals of either energy surplus or deficit (21, 22).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Rebello, 2020, Obesity medications in development, Expert Opin Invest Drugs source

      Not checked in the free run.

    • cites [22] Papathanasiou, 2019, GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans, Eur J Endocrinol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GDF-15 inhibits apoptosis and inflammation, and protects the heart from injury.

    “GDF-15 has also been shown to inhibit apoptosis and inflammation, and protects the heart from injury (36–38).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Schlittenhardt, 2004, Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions, Cell Tissue Res source

      Not checked in the free run.

    • cites [37] Kempf, 2011, GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice, Nat Med source

      Not checked in the free run.

    • cites [38] Kempf, 2006, The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury, Circ Res source

      Not checked in the free run.

32 of 32

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Natali study has conflicting publication years

    Minor

    Table 1 dates the Natali et al. study to 2018, while the corresponding reference lists it as published in 2019.

1 of 1

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References 116 · Cited by 39

Authors
Ouyang, J., Isnard, S., Lin, J., Fombuena, B., Peng, X., Chen, Y., & Routy, J.-P.
Affiliations
  • McGill University Health Centre (CA)
  • Chongqing Public Health Medical Center (CN)
Corresponding author
  • Chen, Yaokai
  • Routy, Jean-Pierre
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2020-11-18
Volume
11
Pages
581839-581839
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2020.581839
PMC
PMC7708317
OpenAlex
W3100687915
Semantic Scholar
45eb856d9c6e0441b379915c2bd43666e9de8e1c
Cited by
39
References
116
Citations by year
2026: 5 · 2025: 3 · 2024: 8 · 2023: 5 · 2022: 8 · 2021: 9 · 2020: 1
FWCI
0.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Styrelsen för Internationellt Utvecklingssamarbete
  • Canadian Institutes of Health Research (grants MOP 103230 and PTJ 166049, CTN PT027, 103230, MOP103230, HB2 – 164064, 166049_1)
Topics
  • Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords
growth differentiation factor 15, metformin, weight loss, obesity, gut-brain axis, dietary intake, diabetes mellitus, anorexia nervosa, pharmacological weight loss
MeSH terms
Diabetes Mellitus, Gene Expression Regulation, Humans, Hypoglycemic Agents, Metformin, Weight Loss, Case-Control Studies, Growth Differentiation Factor 15

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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