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Cited by 148Ovarian function and disordersDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes Treatment and Management

The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome

Open access
Bednarz, Krzysztof, Kowalczyk, Karolina, Cwynar, Marlena, Czapla, Dominika, Czarkowski, Wiktor, Kmita, Dominika, Nowak, Artur, Madej, Paweł·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms23084334PMC PMC9029608
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Abstract

Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes mechanisms and clinical evidence for GLP-1 receptor agonists (GLP-1RAs) in polycystic ovary syndrome (PCOS), focusing on insulin resistance, obesity, inflammation, oxidative stress, lipid metabolism, and reproductive outcomes. It concludes that GLP-1RAs may improve metabolic and reproductive features in obese women with PCOS, but they were not officially approved for PCOS as of March 2022 and further trials are needed.

Key findings

  • Insulin resistance is common in PCOS: clamp studies document it in 75% of women with PCOS; prevalence is 59.3% in normal-weight, 77.5% in overweight, and 93.9% in obese patients, and is higher in the classic phenotype (80.4%) than ovulatory (65.0%) or normoandrogenic (38.1%) phenotypes.
  • GLP-1RAs may reduce body weight and act on insulin-resistance mechanisms by increasing glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. In one trial of 72 women with PCOS and BMI >25 kg/m² and/or IR, 26 weeks of liraglutide decreased body weight by 5.2 kg, reduced liver fat, visceral adipose tissue, and NAFLD prevalence, increased SHBG by 19%, and decreased free testosterone by 19%, but had no influence on measures of IR, glucagon, or adiponectin.
  • Clinical trials report weight loss with liraglutide: after 12 weeks, high-dose liraglutide monotherapy produced −6.3 ± 3.7 kg versus −3.6 ± 2.5 kg for metformin plus low-dose liraglutide; in 32 obese women with PCOS, mean BMI reduction was 2.13 kg/m² with liraglutide versus 0.62 kg/m² with metformin in newly diagnosed PCOS; in 45 obese women with PCOS, liraglutide reduced body weight most (3.1 ± 3.5 kg), decreased visceral adipose tissue area, and improved OGTT outcomes.
  • In infertile obese women with PCOS, liraglutide plus metformin was superior to metformin alone for spontaneous and IVF pregnancy rates, with twice as many patients becoming pregnant over 1 year despite comparable reductions in body weight and adipose tissue. GLP-1RAs were not officially approved for PCOS as of March 2022.

Methods

  • Narrative review focused on the role of GLP-1RAs in PCOS treatment, based on articles from 2010 to 2022.
  • Synthesizes preclinical and clinical evidence, including mechanistic cell and mouse studies and randomized clinical trials; no systematic search strategy, meta-analysis, or formal risk-of-bias assessment is described.

Limitations

  • The paper states that there are no studies on the influence of GLP-1 on oxidative stress specifically in PCOS; the cited oxidative stress studies were carried out in diabetic patients or cells.
  • The paper states that further studies and clinical trials are needed to better understand the role of GLP-1RAs in disease pathomechanism, optimize doses, and identify which patients will benefit most; it also notes that GLP-1RAs were not officially approved for PCOS as of March 2022.
  • Evident from the text: this is a narrative review without a described systematic search, and many cited PCOS trials are small and short-term (e.g., n = 72, 30, 32, 36, 57, 45, 19; 12–26 weeks), limiting generalizability.

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

Integrity signals

Registry

Crossref · 10.3390/ijms23084334

Cites

142 of 142 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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

  • Premisecitation

    Lower adiponectin concentration is associated with the development of insulin resistance and type 2 diabetes mellitus.

    “Its lower concentration is associated with the development of IR and T2DM [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Liu, 2016, Adiponectin, TNF-α and Inflammatory Cytokines and Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis, Cytokine source

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  • Premisecitation

    Hyperandrogenism can increase inflammation through activation of the nuclear factor kappa B (NF-κB) inflammation pathway.

    “Additionally, hyperandrogenism can increase inflammation through activation of the nuclear factor kappa B (NF-κB) inflammation pathway [45,46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Daniels, 2012, Hyperandrogenism Sensitizes Mononuclear Cells to Promote Glucose-Induced Inflammation in Lean Reproductive-Age Women, Am. J. Physiol. Endocrinol. Metab. source

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    • cites [46] Rote, 2010, Elevated Circulating Levels of Macrophage Migration Inhibitory Factor in Polycystic Ovary Syndrome, Cytokine source

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  • Premisecitation

    Adipose tissue growth without adequate vascularization results in hypoxia.

    “Adipose tissue growth without adequate vascularization results in hypoxia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Cifarelli, 2020, Decreased Adipose Tissue Oxygenation Associates with Insulin Resistance in Individuals with Obesity, J. Clin. Investig. source

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  • Premisecitation

    Prenatal exposure to high levels of androgens can probably lead to the development of insulin resistance and PCOS.

    “Moreover, prenatal exposure to high levels of androgens can probably lead to the development of IR and PCOS [53,54,55].”
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    • cites [53] Carrasco, 2020, Prenatal Testosterone Exposure Disrupts Insulin Secretion and Promotes Insulin Resistance, Sci. Rep. source

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    • cites [54] Risal, 2019, Prenatal Androgen Exposure and Transgenerational Susceptibility to Polycystic Ovary Syndrome, Nat. Med. source

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    • cites [55] Ferreira, 2021, Prenatal Testosterone Exposure Induces Insulin Resistance, Uterine Oxidative Stress and pro-Inflammatory Status in Rats, Mol. Cell Endocrinol. source

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  • Premisecitation

    TNF-α affects insulin signaling by phosphorylation of serine in IRS-1 through activation of several serine kinases, including JNK and ERK, which inhibits insulin-induced tyrosine phosphorylation of IRS-1 and downregulates PI3K activity.

    “TNF-α affects insulin signaling by phosphorylation of serine in IRS-1 through activation of several serine kinases, including c-Jun-NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), which inhibits insulin-induced tyrosine phosphorylation of IRS-1 and downregulates PI3K activity [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Shibata, 2013, Inhibition of the TNF-α-Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR, J. Pharmacol. Sci. source

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  • Classified as probably not a substantial claim. 10

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    Premisecitation

    Mitochondrial damage, increased oxidative stress, and endoplasmic reticulum stress are involved in the development of insulin resistance.

    “Moreover, mitochondrial damage, increased oxidative stress, and endoplasmic reticulum stress are also involved in the development of IR [50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Yaribeygi, 2019, Insulin Resistance: Review of the Underlying Molecular Mechanisms, J. Cell Physiol. source

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

    Premisecitation

    Metabolic inflexibility is the impaired ability to switch from lipid to carbohydrate oxidation under insulin-stimulated conditions, and this state is associated with insulin resistance.

    “Metabolic inflexibility is the impaired ability to switch from lipid to carbohydrate oxidation under insulin-stimulated conditions. This state is associated with IR.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Adamska, 2013, Normal Metabolic Flexibility despite Insulin Resistance Women with Polycystic Ovary Syndrome, Endocr. J. source

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    Premisecitation

    Chronic inflammation develops with increased levels of TNF-α, MCP-1, CRP, IL-1, IL-6, and other pro-inflammatory cytokines, which have been found elevated in PCOS.

    “Chronic inflammation also develops with increased levels of tumor necrosis factor α (TNF-α), monocyte chemotactic protein-1 (MCP-1), C-reactive protein (CRP), interleukin-1 (IL-1), interleukin-6 (IL-6), and other pro-inflammatory cytokines, which have been found elevated in PCOS.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Daniels, 2012, Hyperandrogenism Sensitizes Mononuclear Cells to Promote Glucose-Induced Inflammation in Lean Reproductive-Age Women, Am. J. Physiol. Endocrinol. Metab. source

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    • cites [46] Rote, 2010, Elevated Circulating Levels of Macrophage Migration Inhibitory Factor in Polycystic Ovary Syndrome, Cytokine source

      Not checked in the free run.

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    Premisecitation

    Activation of androgen receptors by dihydrotestosterone in the brains of mice led to the development of insulin resistance, whereas rodents deprived of these receptors did not develop this disorder.

    “Studies on mice have shown that activation of androgen receptors by dihydrotestosterone in the brains of the tested animals led to the development of IR, whereas rodents deprived of these receptors did not develop this type of disorder.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Navarro, 2018, Androgen Excess in Pancreatic β Cells and Neurons Predisposes Female Mice to Type 2 Diabetes, JCI Insight source

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    Premisecitation

    In PCOS, insulin resistance is present in obese and overweight patients, as well as in those of normal weight, although in the latter group with a lower frequency (59.3% in normal weight vs. 77.5% in overweight and 93.9% in obese patients).

    “In PCOS, IR is present in obese and overweight patients, as well as in those of normal weight, although in the latter group, with a lower frequency (59.3% in normal weight vs. 77.5% in overweight and 93.9% in obese patients) [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Tosi, 2017, Insulin Resistance in a Large Cohort of Women with Polycystic Ovary Syndrome: A Comparison between Euglycaemic-Hyperinsulinaemic Clamp and Surrogate Indexes, Hum. Reprod. source

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    Premisecitation

    Some data show that PCOS women have normal metabolic flexibility, which could suggest a distinct pathophysiological mechanism for insulin resistance in this group.

    “However, some data show that PCOS women have normal metabolic flexibility, which could suggest a distinct pathophysiological mechanism for IR in this group [51].”
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    • cites [51] Adamska, 2013, Normal Metabolic Flexibility despite Insulin Resistance Women with Polycystic Ovary Syndrome, Endocr. J. source

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    Interpretationcitation

    The result of the described processes is impaired glucose transport into cells by insulin-dependent membrane GLUT 4 transporters, reduced glycogen synthesis and decreased inhibition of hepatic gluconeogenesis, leading to hyperglycemia and compensatory hyperinsulinemia.

    “The result of all the processes described above is impaired glucose transport into cells by insulin-dependent membrane GLUT 4 transporters, reduced glycogen synthesis and decreased inhibition of hepatic gluconeogenesis. This leads to hyperglycemia and to compensatory hyperinsulinemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Moghetti, 2021, Insulin Resistance and PCOS: Chicken or Egg?, J. Endocrinol. Investig. source

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    Interpretationcitation

    Insulin resistance, the resulting hyperinsulinemia, and increased androgen levels influence each other, and it is difficult to determine which phenomenon occurs first.

    “IR, the resulting hyperinsulinemia, and increased androgen levels influence each other, and it is difficult to determine which phenomenon occurs first (Figure 4) [61].”
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    • cites [61] Moghetti, 2021, Insulin Resistance and PCOS: Chicken or Egg?, J. Endocrinol. Investig. source

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    Premisecitation

    TNF-α causes decreased GLUT-4 expression and decreased glucose transport into cells.

    “It causes decreased GLUT-4 expression and decreased glucose transport into cells (Figure 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Shibata, 2013, Inhibition of the TNF-α-Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR, J. Pharmacol. Sci. source

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    Premisecitation

    An altered profile of miRNA particles in plasma has been observed in PCOS.

    “An altered profile of miRNA particles in plasma has been observed in PCOS [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Jiang, 2021, Differential Expression Profile of Plasma Exosomal MicroRNAs in Women with Polycystic Ovary Syndrome, Fertil. Steril. source

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    Premisecitation

    Insulin affects the hypothalamic-pituitary system by increasing the frequency and amplitude of GnRH release pulses and, in consequence, LH release, which stimulates ovarian cells to androgen synthesis.

    “Moreover, insulin affects the hypothalamic-pituitary system. Through MAPK and increased gonadotropin-releasing hormone (GnRH) gene expression, it increases the frequency and amplitude of GnRH release pulses and, in consequence, LH release, which stimulates ovarian cells to androgen synthesis [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Kim, 2005, Insulin Regulation of GnRH Gene Expression through MAP Kinase Signaling Pathways, Mol. Cell. Endocrinol. source

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    Premisecitation

    GLP-1R is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain, and the localization of these receptors determines GLP-1RAs effects.

    “GLP-1R is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain, and the localization of these receptors determines GLP-1RAs effects [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Knudsen, 2019, The Discovery and Development of Liraglutide and Semaglutide, Front. Endocrinol. source

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    Premisecitation

    In vagotomized animals, the effect of liraglutide on body weight has not been compromised, supporting the hypothesis that gut-to-brain communication via the vagal nerve is not the main mechanism responsible for the weight loss.

    “However, in vagotomized animals, the effect of liraglutide on body weight has not been compromised, supporting the hypothesis that gut-to-brain communication via the vagal nerve is not the main mechanism responsible for the weight loss [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Knudsen, 2019, The Discovery and Development of Liraglutide and Semaglutide, Front. Endocrinol. source

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    Premisecitation

    GLP-1 binds to insulin receptors on beta cells and stimulates insulin secretion.

    “This hormone binds to insulin receptors on the beta cells and stimulates insulin secretion [67,68,69].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [67] Nadkarni, 2014, Regulation of Glucose Homeostasis by GLP-1, Prog. Mol. Biol. Transl. Sci. source

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    • cites [68] Meloni, 2013, GLP-1 Receptor Activated Insulin Secretion from Pancreatic β-Cells: Mechanism and Glucose Dependence, Diabetes Obes. Metab. source

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    • cites [69] Finan, 2019, Glucagon-like Peptide 1 (GLP-1), Mol. Metab. source

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    Premisecitation

    SHBG can be useful as a marker for a higher risk of PCOS.

    “Studies indicate that SHBG can be useful as a marker for a higher risk of PCOS [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Deswal, 2018, Sex Hormone Binding Globulin—An Important Biomarker for Predicting PCOS Risk: A Systematic Review and Meta-Analysis, Syst. Biol. Reprod. Med. source

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    Premisecitation

    GLP-1RAs treatment reduces body weight and diminishes the risk of cardiovascular disease (CVD).

    “The GLP-1RAs treatment reduces body weight and diminishes the risk of cardiovascular disease (CVD) [71,72].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] Zhao, 2013, Glucagon-like Peptide-1 (GLP-1) and Protective Effects in Cardiovascular Disease: A New Therapeutic Approach for Myocardial Protection, Cardiovasc. Diabetol. source

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    • cites [72] Ijzerman, 2014, Effects of Glucagon-like Peptide 1 on Appetite and Body Weight: Focus on the CNS, J. Endocrinol.

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    Premisecitation

    GLP-1RAs decrease low-density lipoprotein (LDL) and triglyceride (TG) levels.

    “Furthermore, GLP-1RAs are metabolically beneficial because they decrease low-density lipoprotein (LDL) and TG levels [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Finan, 2019, Glucagon-like Peptide 1 (GLP-1), Mol. Metab. source

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    Premisecitation

    Incretin mimetics stimulate insulin secretion, decrease glucagon secretion, inhibit the hunger center, and delay gastric emptying, thereby improving postprandial glucose levels and causing earlier satiety.

    “The incretin mimetics stimulate insulin secretion, decrease glucagon secretion, inhibit the hunger center, and delay gastric emptying, thereby the postprandial glucose levels improve, and the feeling of satiety appears earlier [69] (Figure 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Finan, 2019, Glucagon-like Peptide 1 (GLP-1), Mol. Metab. source

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    Premisecitation

    GLP-1RAs are a group of drugs that imitate the activity of the incretin hormone GLP-1 secreted in the distal part of the small intestine.

    “The GLP-1RAs, also known as incretin mimetics, are a group of drugs that imitate the activity of the incretin hormone GLP-1 secreted in the distal part of the small intestine [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Nadkarni, 2014, Regulation of Glucose Homeostasis by GLP-1, Prog. Mol. Biol. Transl. Sci. source

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    Premisecitation

    GLP-1 does not demonstrate activity when blood glucose levels are normal or in cases of hypoglycaemia.

    “The GLP-1 does not demonstrate activity when blood glucose levels are normal or in cases of hypoglycaemia [70].”
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    • cites [70] Pfeiffer, 2018, High Glycemic Index Metabolic Damage—A Pivotal Role of GIP and GLP-1, Trends Endocrinol. Metab. source

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    Premisecitation

    GLP-1RAs decrease blood glucose levels, but they do not cause hypoglycemia.

    “The GLP-1RAs decrease blood glucose levels, but they do not cause hypoglycemia [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Meloni, 2013, GLP-1 Receptor Activated Insulin Secretion from Pancreatic β-Cells: Mechanism and Glucose Dependence, Diabetes Obes. Metab. source

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    Premisecitation

    Exacerbation of the symptoms of PCOS is associated with the concomitant presence of obesity, which further increases hyperinsulinemia.

    “Additionally, exacerbation of the symptoms of PCOS is associated with the concomitant presence of obesity, which further increases hyperinsulinemia [84,87].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Cena, 2020, Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists, J. Clin. Endocrinol. Metabolism. Endocr. Soc. source

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    • cites [87] Moran, 2015, Metabolic Risk in PCOS: Phenotype and Adiposity Impact, Trends Endocrinol. Metab. source

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    Premisecitation

    GLP-1RAs have positive effects in patients with PCOS, decreasing insulin resistance and improving metabolic alterations.

    “The GLP-1RAs also have positive effects in patients with PCOS decreasing IR and improving metabolic alterations [80,81,82,83].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [80] Glintborg, 2020, Medical Treatment and Comorbidity in Polycystic Ovary Syndrome: An Updated Review, Curr. Opin. Endocr. Metab. Res. source

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    • cites [81] Siamashvili, 2021, Update on the Effects of GLP-1 Receptor Agonists for the Treatment of Polycystic Ovary Syndrome, Expert Rev. Clin. Pharmacol. source

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    • cites [82] Nylander, 2017, Effects of Liraglutide on Ovarian Dysfunction in Polycystic Ovary Syndrome: A Randomized Clinical Trial, Reprod. Biomed. Online source

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    • cites [83] Kahal, H., Aburima, A., Ungvari, T., Rigby, A.S., Coady, A.M., Vince, R.V., Ajjan, R.A., Kilpatrick, E.S., Naseem, K.M., and Atkin, S.L. (2015). The Effects of Treatment with Liraglutide on Atherothrombotic Risk in Obese Young Women with Polycystic Ovary Syndrome and Controls. BMC Endocr. Disord., 15. source

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    Premisecitation

    Long-term negative energy balance achieved by a reduction in appetite and energy intake, increase in energy expenditure, or both are required to achieve body weight loss.

    “Long-term negative energy balance achieved by a reduction in appetite and energy intake, increase in energy expenditure, or both are required to achieve body weight loss [72].”
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    • cites [72] Ijzerman, 2014, Effects of Glucagon-like Peptide 1 on Appetite and Body Weight: Focus on the CNS, J. Endocrinol.

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    Interpretationcitation

    PCOS does not appear in every woman with IR or hyperinsulinemia and not every woman suffering from PCOS presents IR, suggesting that there must be another malfunction that favors androgen excess in response to insulin or other triggering factors.

    “However, the fact that PCOS does not appear in every woman with IR or hyperinsulinemia and the fact that not every woman suffering from PCOS presents IR, suggests that there must be another malfunction that favors androgen excess in response to insulin or other triggering factors [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 2018, Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment, Nat. Rev. Endocrinol. source

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    Premisecitation

    In a study of 72 women with PCOS, with a BMI > 25 kg/m2 and/or insulin resistance, 26 weeks of liraglutide treatment decreased body weight by 5.2 kg and reduced liver fat content, visceral adipose tissue, and the prevalence of NAFLD.

    “The research on the impact of liraglutide on ectopic fat in the group of 72 women with PCOS, with a BMI > 25 kg/m2 and/or IR showed that 26 weeks of liraglutide treatment decreased body weight by 5.2 kg and pointedly reduced liver fat content, visceral adipose tissue, and the prevalence of NAFLD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Nylander, 2018, Effect of Liraglutide on Ectopic Fat in Polycystic Ovary Syndrome: A Randomized Clinical Trial, Diabetes Obes. Metab. source

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  • May combine two claims.

    Interpretationcitation

    There are vagal GLP-1R sensory neurons that do not exhibit acute responses to liraglutide and semaglutide, therefore gastric emptying seems unlikely to be the main mechanism by which GLP-1RA affects weight loss.

    “However, there are vagal GLP-1R sensory neurons that do not exhibit acute responses to liraglutide and semaglutide, therefore this seems unlikely to be the main mechanism by which GLP-1RA affects weight loss [90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Drucker, 2018, Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1, Cell Metabolism. source

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    Premisecitation

    The non-hyperandrogenic phenotype presents with oligo-ovulation, PCOM and has the weakest connection with IR and metabolic comorbidities.

    “The least severe is the non-hyperandrogenic phenotype, which presents with oligo-ovulation, PCOM and has the weakest connection with IR and metabolic comorbidities [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 2018, Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment, Nat. Rev. Endocrinol. source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Insulin resistance in PCOS results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: excess visceral fat, chronic inflammation, and reactive oxygen species.

    “Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Using GLP-1RAs leads to a reduction in weight, testosterone levels, and improves ovulation among obese patients.

    “Using GLP-1RAs leads to a reduction in weight, testosterone levels, and improves ovulation among obese patients [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Niafar, 2016, A Systematic Review of GLP-1 Agonists on the Metabolic Syndrome in Women with Polycystic Ovaries, Arch. Gynecol. Obstet. source

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  • May combine two claims.

    Premisecitation

    In the same study, liraglutide increased SHBG levels by 19% and decreased free testosterone by 19%.

    “Furthermore, liraglutide increased SHBG levels by 19% and decreased free testosterone by 19%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Nylander, 2018, Effect of Liraglutide on Ectopic Fat in Polycystic Ovary Syndrome: A Randomized Clinical Trial, Diabetes Obes. Metab. source

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  • May combine two claims.

    Premisecitation

    Hyperinsulinemia is the main reason for increased androgen secretion because insulin acts as a co-gonadotropin on the ovary, facilitates androgen secretion from the adrenal glands, and modulates releasing of luteinizing hormone (LH).

    “It is believed that hyperinsulinemia is the main reason for increased androgen secretion because insulin acts as a co-gonadotropin on the ovary, facilitates androgen secretion from the adrenal glands, and modulates releasing of luteinizing hormone (LH) [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] 2018, Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment, Nat. Rev. Endocrinol. source

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    Premisecitation

    The classic phenotype of PCOS consists of hyperandrogenism and oligo-ovulation and is linked with the most severe insulin resistance and metabolic comorbidities.

    “The classic phenotype consists of hyperandrogenism and oligo-ovulation. It is linked with the most severe insulin resistance and metabolic comorbidities.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 2018, Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment, Nat. Rev. Endocrinol. source

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  • May combine two claims.

    Premisecitation

    Intra-VTA and intra-NAc injections of GLP-1RA (exendin-4) reduced intake of regular chow, high-fat diet, and body weight.

    “Intra-VTA and intra-NAc injections of GLP-1RA (exendin-4) reduced intake of regular chow, high-fat diet, and body weight.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Kanoski, 2016, GLP-1 and Weight Loss: Unraveling the Diverse Neural Circuitry, Am. J. Physiol. Regul. Integr. Comp. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same study, HbA1c, fasting glucose, and leptin decreased, but there was no influence on measures of insulin resistance, glucagon, and adiponectin.

    “HbA1c, fasting glucose, and leptin also decreased, but there was no influence on measures of IR, glucagon, and adiponectin [93].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Nylander, 2018, Effect of Liraglutide on Ectopic Fat in Polycystic Ovary Syndrome: A Randomized Clinical Trial, Diabetes Obes. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits NPY and AgRP and increases measures of satiety, and decreases hunger.

    “Subsequently, GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits NPY and AgRP and increases measures of satiety, and decreases hunger [92].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Ard, 2021, Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists, Adv. Ther. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same study, the incidence of periods improved (bleeding ratio 0.28 vs. 0.14 placebo) and ovarian volume was reduced by 1.6 mL.

    “The incidence of periods improved (bleeding ratio 0.28 vs. 0.14 placebo) and ovarian volume was reduced by 1.6 mL [82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Nylander, 2017, Effects of Liraglutide on Ovarian Dysfunction in Polycystic Ovary Syndrome: A Randomized Clinical Trial, Reprod. Biomed. Online source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that trial, liraglutide treatment had a better influence on BMI and waist circumference reduction than combined therapy, but the latter significantly decreased total testosterone and caused less nausea.

    “Liraglutide treatment had a better influence on BMI and waist circumference reduction than combined therapy, but the latter significantly decreased total testosterone and caused less nausea [94].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Jensterle, M., Kravos, N.A., Goričar, K., and Janez, A. (2017). Short-Term Effectiveness of Low Dose Liraglutide in Combination with Metformin versus High Dose Liraglutide Alone in Treatment of Obese PCOS: Randomized Trial. BMC Endocr. Disord., 17. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    GLP-1RAs are supposed to decrease food cravings, preference for energy-dense foods and also prevent overeating.

    “Thanks to alterations in the food reward pathway, they are supposed to decrease food cravings, preference for energy-dense foods and also prevent overeating [91].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Kanoski, 2016, GLP-1 and Weight Loss: Unraveling the Diverse Neural Circuitry, Am. J. Physiol. Regul. Integr. Comp. Physiol. source

      Not checked in the free run.

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

    Premisecitation

    The ovulatory PCOS phenotype comprises hyperandrogenism and PCOM and co-occurs with moderate IR and metabolic dysfunction.

    “The next phenotype is ovulatory PCOS which comprises hyperandrogenism and PCOM. It co-occurs with moderate IR and metabolic dysfunction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 2018, Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment, Nat. Rev. Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP-1RAs do not broadly cross the blood-brain barrier, but they can access neurons in the circumventricular organs and in a few select sites in the hypothalamus.

    “GLP-1RAs do not broadly cross the blood-brain barrier, but they can access neurons in the CVO’s and in a few select sites in the hypothalamus [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Knudsen, 2019, The Discovery and Development of Liraglutide and Semaglutide, Front. Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study of 36 women pre-treated with metformin, after 12 weeks, liraglutide decreased the uncontrolled eating score and emotional eating score, which additionally influenced body weight loss (3.8 ± 0.1 kg).

    “The study concerning the impact of liraglutide on eating behavior was performed on a group of 36 women pre-treated with metformin. After 12 weeks, it turned out that liraglutide decreased the uncontrolled eating score and emotional eating score, which additionally influenced body weight loss (3.8 ± 0.1 kg) [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Jensterle, 2015, Short-Term Intervention with Liraglutide Improved Eating Behavior in Obese Women with Polycystic Ovary Syndrome, Endocr. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP-1RAs administration reduced feelings of hunger, and it was associated with an increase in functional connectivity of the NTS with the hypothalamus.

    “GLP-1RAs administration reduced feelings of hunger, and it was associated with an increase in functional connectivity of the NTS with the hypothalamus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Ard, 2021, Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists, Adv. Ther. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A large clinical trial data set with GLP-1RAs has shown that many patients have weight loss and no side effects, hence, GI side effects are not the main mechanism of weight loss.

    “A large clinical trial data set with GLP-1RAs has shown that many patients have weight loss and no side effects, hence, GI side effects are not the main mechanism of weight loss [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Knudsen, 2019, The Discovery and Development of Liraglutide and Semaglutide, Front. Endocrinol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    GLP1-RAs tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia.

    “They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    GLP1-RAs not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism.

    “Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    GLP-1 receptor agonists decrease energy intake and reduce adipose tissue.

    “GLP-1RAs decrease energy intake and provide adipose tissue reduction [114].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Inoue, 2011, Short-Term Effects of Liraglutide on Visceral Fat Adiposity, Appetite, and Food Preference: A Pilot Study of Obese Japanese Patients with Type 2 Diabetes, Cardiovasc. Diabetol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liraglutide enters the brain in a GLP-1R-dependent manner, and a fluorescent version of liraglutide was observed in the hypothalamus and several circumventricular organs.

    “Liraglutide enters the brain in a GLP-1R-dependent manner, and a fluorescent version of liraglutide was observed in the hypothalamus (ARC, paraventricular nucleus (PVN), supraoptic NTS, supraoptic decussation) and several circumventricular organs (CVOs, e.g., median eminence (ME), area postrema (AP), subfornical organ, and organum vasculosum of lamina terminalis).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Knudsen, 2019, The Discovery and Development of Liraglutide and Semaglutide, Front. Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.

    “GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a trial with 30 women comparing high dose liraglutide to metformin combined with low dose liraglutide, after 12 weeks, both treatment schedules brought considerable weight loss (−6.3 ± 3.7 kg monotherapy vs. −3.6 ± 2.5 kg combined therapy) and improved outcome of OGTT.

    “A trial with 30 women that compared the impact of a high dose of liraglutide to metformin combined with low dose of liraglutide on weight loss showed that after 12 weeks, both treatment schedules brought considerable weight loss (−6.3 ± 3.7 kg monotherapy vs. −3.6 ± 2.5 kg combined therapy) and improved outcome of OGTT.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Jensterle, M., Kravos, N.A., Goričar, K., and Janez, A. (2017). Short-Term Effectiveness of Low Dose Liraglutide in Combination with Metformin versus High Dose Liraglutide Alone in Treatment of Obese PCOS: Randomized Trial. BMC Endocr. Disord., 17. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies support the concept that GLP-1R in the brain is mainly responsible for decreased food intake and further positive effect of GLP-1RAs on weight loss.

    “Studies support the concept that GLP-1R in the brain is mainly responsible for decreased food intake and further positive effect of GLP-1RAs on weight loss [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Knudsen, 2019, The Discovery and Development of Liraglutide and Semaglutide, Front. Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    GLP-1 receptor agonists affect adipose tissue metabolism both by directly modulating preadipocyte differentiation and by mediating lipid metabolism processes, resulting in reduced lipogenesis and stimulated lipolysis.

    “To summarize, GLP-1RAs affect the metabolism of adipose tissue in both ways, by directly modulating preadipocyte differentiation and by mediating lipid metabolism processes, resulting in a reduction of lipogenesis and stimulation of lipolysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    GLP-1 receptor agonists can modulate LH, either increasing LH surge in HPO axis disturbances due to adipose tissue estrogen aromatization or decreasing high LH levels connected with hyperinsulinemia.

    “Based on the research regarding the impact of GLP-1Ras on the LH ratio presented above, we postulate its modulating abilities. It can either increase LH surge in HPO axis disturbances due to adipose tissue estrogen aromatization or decrease too high LH levels (inducing ovarian androgen secretion) connected with hyperinsulinemia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In infertile obese women with PCOS, liraglutide plus metformin is superior to metformin alone in increasing spontaneous and in vitro fertilization pregnancy rates, while both treatments produce comparable reduction in body weight and adipose tissue.

    “Results have shown that double therapy was superior to metformin alone in increasing spontaneous pregnancies and in vitro fertilization pregnancy rates, wherein both treatment strategies resulted in comparable reduction in body weight and adipose tissue.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Salamun, 2018, Liraglutide Increases IVF Pregnancy Rates in Obese PCOS Women with Poor Response to First-Line Reproductive Treatments: A Pilot Randomized Study, Eur. J. Endocrinol. source

      Not checked in the free run.

54 of 54

  • The paper relies on this without support.

    Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS).

    “Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS).”

  • The paper relies on this without support.

    GLP-1RAs release glucose-dependent insulin from the pancreatic cells.

    “GLP-1RAs release glucose-dependent insulin from the pancreatic cells.”

  • The paper relies on this without support.

    Insulin resistance is not included in the diagnostic criteria of PCOS.

    “Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis.”

  • The paper relies on this without support.

    Mechanisms of GLP-1 receptor agonist action observed in animal models and cell lines apply to women with PCOS.

    “The undermentioned studies were carried out on a group of diabetic patients [125,126] or cells [127,128].”

  • The paper relies on this without support.

    Findings on GLP-1 receptor agonist effects in diabetic patients generalize to women with PCOS.

    “Unfortunately, there are no studies on the influence of GLP-1 on oxidative stress in PCOS. The undermentioned studies were carried out on a group of diabetic patients [125,126] or cells [127,128].”
5 of 5

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?

  • While GLP-1RAs may not outperform metformin in managing hormone levels, they are still beneficial in populations not already treated with metformin.

    “This suggests that while GLP-1RAs may not outperform metformin in managing hormone levels, they are still beneficial in populations not already treated with metformin23–26.”

    From Efficacy and safety of GLP-1 receptor agonists on weight management and metabolic parameters in PCOS women: a meta-analysis of randomized controlled trials (2025) · cites this paper as [26]

    Section 3.1 (page not provided) reports greater weight loss with liraglutide than metformin in women with newly diagnosed PCOS, but does not establish that they had never received metformin. It also reports a testosterone reduction with combination treatment, not a direct finding that GLP-1RAs fail to outperform metformin on hormone levels. Section 3.3 (page not provided) instead reports improved androgen bioavailability with combination treatment versus metformin alone. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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.

  • Conflicting comparisons of combination therapy and metformin alone

    Minor

    The paper first says the two treatments produced comparable reductions in BMI and visceral adipose tissue, then describes the combination treatment as superior on those same measures compared with metformin alone.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Carolo, 2017, O Aconselhamento Nutricional Promove Mudanças Nos Hábitos Alimentares de Adolescentes Com Excesso de Peso e Obesas e Com Síndrome Dos Ovários Policísticos, Rev. Bras. Ginecol. Obstet., 39, 692

Cited by

Sorted by citations

Related

Authors
Bednarz, K., Kowalczyk, K., Cwynar, M., Czapla, D., Czarkowski, W., Kmita, D., Nowak, A., & Madej, P.
Affiliations
  • Medical University of Silesia (PL)
  • Gynecological and Obstetrician Polyclinic, District Hospital, 15-435 Białystok, Poland
Corresponding author
Kowalczyk, Karolina
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-04-14
Volume
23
Issue
8
Pages
4334
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms23084334
PMC
PMC9029608
OpenAlex
W4224024335
Semantic Scholar
4ea5a9067c4b3ac0a28b29dac2bb917cdf54e1bf
Cited by
148
References
142
Citations by year
2026: 34 · 2025: 44 · 2024: 46 · 2023: 16 · 2022: 7 · 2018: 1
FWCI
4.55
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
polycystic ovary syndrome, insulin resistance, obesity, GLP-1 receptor agonists, weight loss, insulin receptor signaling, glucose transporters, inflammation, oxidative stress, lipid metabolism, luteinizing hormone surge, hyperinsulinemia, obesity pharmacotherapy
MeSH terms
Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Female, Humans, Inflammation, Insulin, Insulin Resistance, Obesity, Polycystic Ovary Syndrome, Anti-Obesity Agents

About these checks

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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