Adipokines as a therapeutic target by metformin to improve metabolic function: A systematic review of randomized controlled trials

Dludla, Phiwayinkosi V.; Nkambule, Bongani B.; Mazibuko-Mbeje, Sithandiwe E.; Nyambuya, Tawanda M.; Mxinwa, Vuyolwethu; Mokgalaboni, Kabelo; Ziqubu, Khanyisani; Cirilli, Ilenia; Marcheggiani, Fabio; Louw, Johan; Tiano, Luca

doi:10.1016/j.phrs.2020.105219

Cited by 41 publications

(23 citation statements)

References 47 publications

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“…112 Metformin increases the bioavailability of adiponectin that can maintain body composition and prevent excessive fat accumulation (Figure 2). 113,114 As mentioned previously, the drug increases the plasma levels of GLP-1 in both diabetic and nondiabetic patients (Figure 2). 115,116 GLP-1 receptor agonists could lead to pronounced weight loss in previous clinical trials.…”

Section: ■ Metformin and Obesitysupporting

confidence: 59%

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Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next?

Ala

2021

ACS Pharmacol. Transl. Sci.

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Diabetes is accompanied by several complications. Higher prevalence of cancers, cardiovascular diseases, chronic kidney disease (CKD), obesity, osteoporosis, and neurodegenerative diseases has been reported among patients with diabetes. Metformin is the oldest oral antidiabetic drug and can improve coexisting complications of diabetes. Clinical trials and observational studies uncovered that metformin can remarkably prevent or alleviate cardiovascular diseases, obesity, polycystic ovarian syndrome (PCOS), osteoporosis, cancer, periodontitis, neuronal damage and neurodegenerative diseases, inflammation, inflammatory bowel disease (IBD), tuberculosis, and COVID-19. In addition, metformin has been proposed as an antiaging agent. Numerous mechanisms were shown to be involved in the protective effects of metformin. Metformin activates the LKB1/AMPK pathway to interact with several intracellular signaling pathways and molecular mechanisms. The drug modifies the biologic function of NF-κB, PI3K/AKT/mTOR, SIRT1/PGC-1α, NLRP3, ERK, P38 MAPK, Wnt/β-catenin, Nrf2, JNK, and other major molecules in the intracellular signaling network. It also regulates the expression of noncoding RNAs. Thereby, metformin can regulate metabolism, growth, proliferation, inflammation, tumorigenesis, and senescence. Additionally, metformin modulates immune response, autophagy, mitophagy, endoplasmic reticulum (ER) stress, and apoptosis and exerts epigenetic effects. Furthermore, metformin protects against oxidative stress and genomic instability, preserves telomere length, and prevents stem cell exhaustion. In this review, the protective effects of metformin on each disease will be discussed using the results of recent meta-analyses, clinical trials, and observational studies. Thereafter, it will be meticulously explained how metformin reprograms intracellular signaling pathways and alters molecular and cellular interactions to modify the clinical presentations of several diseases.

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Section: ■ Metformin and Obesitysupporting

confidence: 59%

“…Metformin increases the bioavailability of adiponectin that can maintain body composition and prevent excessive fat accumulation (Figure ). , …”

Section: Metformin and Obesitymentioning

confidence: 99%

Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next?

Ala

2021

ACS Pharmacol. Transl. Sci.

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“…From these studies, major pathogenic adipokines associated with metabolic syndrome can be specified, and therapeutic approaches to modify the expression and course of metabolic syndrome and its associated mechanisms can be followed. The favorable consequences for metabolic syndrome of several anti-diabetic medications such as metformin and thiazolidinedione, along with modulation of the levels of adipokines, have been demonstrated [48,85,168]. Further therapeutic options focusing particularly on the selective beneficial effects of adipokines should be developed in the future.…”

Section: Future Perspectivementioning

confidence: 99%

The Roles and Associated Mechanisms of Adipokines in Development of Metabolic Syndrome

Kim

et al. 2022

Molecules

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Metabolic syndrome is a cluster of metabolic indicators that increase the risk of diabetes and cardiovascular diseases. Visceral obesity and factors derived from altered adipose tissue, adipokines, play critical roles in the development of metabolic syndrome. Although the adipokines leptin and adiponectin improve insulin sensitivity, others contribute to the development of glucose intolerance, including visfatin, fetuin-A, resistin, and plasminogen activator inhibitor-1 (PAI-1). Leptin and adiponectin increase fatty acid oxidation, prevent foam cell formation, and improve lipid metabolism, while visfatin, fetuin-A, PAI-1, and resistin have pro-atherogenic properties. In this review, we briefly summarize the role of various adipokines in the development of metabolic syndrome, focusing on glucose homeostasis and lipid metabolism.

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“…In patients with T2DM, adiponectin mRNA levels are significantly reduced and this was associated with a decrease in the expression of NF‐κB, suggesting a link between the two in the pathogenesis of T2DM (Zuo, 2018). The mode of action of the antidiabetic drug, metformin, was found to be through upregulation of adiponectin levels in patients with metabolic syndrome including T2DM (Dludla et al., 2020). Direct administration of adiponectin was also found to be enough to alleviate insulin resistance, reduce fasting blood glucose levels and triglyceride levels in HFD‐fed mice (Li, Zhang, et al., 2020).…”

Section: Physiological Factors That Play Key Roles In the Comorbiditymentioning

confidence: 99%

Pathophysiology linking depression and type 2 diabetes: Psychotherapy, physical exercise, and fecal microbiome transplantation as damage control

Subba

Sandhir

Singh

et al. 2021

Eur J of Neuroscience

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Diabetes increases the likelihood of developing depression and vice versa. Research on this bidirectional association has somewhat managed to delineate the interplay among implicated physiological processes. Still, further exploration is required in this context. This review addresses the comorbidity by investigating suspected common pathophysiological mechanisms. One such factor is psychological stress which disturbs the hypothalamic–pituitary–adrenal axis causing hormonal imbalance. This includes elevated cortisol levels, a common biomarker of both depression and diabetes. Disrupted insulin signaling drives the hampered neurotransmission of serotonin, dopamine, and norepinephrine. Also, adipokine hormones such as adiponectin, leptin, and resistin and the orexigenic hormone, ghrelin, are involved in both depression and T2DM. This disarray further interferes with physiological processes encompassing sleep, the gut–brain axis, metabolism, and mood stability. Behavioral coping mechanisms, such as unhealthy eating, mediate disturbed glucose homeostasis, and neuroinflammation. This is intricately linked to oxidative stress, redox imbalance, and mitochondrial dysfunction. However, interventions such as psychotherapy, physical exercise, fecal microbiota transplantation, and insulin‐sensitizing agents can help to manage the distressing condition. The possibility of glucagon‐like peptide 1 possessing a therapeutic role has also been discussed. Nonetheless, there stands an urgent need for unraveling new correlating targets and biological markers for efficient treatment.

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Adipokines as a therapeutic target by metformin to improve metabolic function: A systematic review of randomized controlled trials

Cited by 41 publications

References 47 publications

Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next?

Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next?

The Roles and Associated Mechanisms of Adipokines in Development of Metabolic Syndrome

Pathophysiology linking depression and type 2 diabetes: Psychotherapy, physical exercise, and fecal microbiome transplantation as damage control

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