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Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies

Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA
Division of Endocrinology, Diabetes and Metabolism, University of South Carolina School of Medicine, Columbia, SC 29208, USA
Department of Diabetes, Nutrition and Metabolic Diseases, Faculty of Medicine, Carol Davila University, 8 Eroii Sanitari, 059474 Bucharest, Romania
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, 90133 Palermo, Italy
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(18), 10038;
Original submission received: 9 September 2021 / Accepted: 14 September 2021 / Published: 17 September 2021
(This article belongs to the Special Issue Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies 2.0)
The metabolic syndrome (MetS) consists of a cluster of metabolic abnormalities including central obesity, insulin resistance, glucose intolerance, hypertension, and atherogenic dyslipidemia [1]; it is rapidly emerging as a global health problem that increases the risk of developing type 2 diabetes and cardiovascular diseases [2]. An early recognition using clinical parameters and inflammatory markers is imperative in order to reduce morbidity and possibly mortality too, attributable to the syndrome. In addition, a number of susceptibility genes and adipokines have been identified that are thought to play a role in the genetic etiology of MetS, thus paving the way to new molecular insights [3,4,5]. Knowledge of the etiopathogenic pathways could facilitate novel therapeutic approaches to managing and treating MetS.
The link between MetS and diabetes and its complications, such as cardiovascular diseases, is a newly developing paradigm with the central point being early atherosclerosis and endovascular inflammation, where atherogenic dyslipidemia seems to have a critical role [6]. LDL seems to be pivotal for the formation and progression of atherosclerotic plaques; however, LDL are not homogenous particles, since they differ for many important pro-atherogenic properties, including metabolic behaviour, affinity to the LDL receptor and susceptibility to oxidation [7]. Indeed, small, dense LDL particles are those with stronger atherogenic potential, and recognized as an independent risk factor for cardiovascular diseases [8].
This highlights the clinical importance of both quality and quantity of LDL. Patients at higher cardiovascular risk have elevated concentrations of small, dense LDL [9,10,11,12,13], which are strictly linked to the early stages of subclinical atherosclerosis and endothelial dysfunction, both enhancing the risk of cardiovascular events [14]. Of interest, some novel anti-diabetic agents have shown favorable effects in subjects with the MetS [15] due to an improvement of patho-physiological alterations [16,17], and increasing evidence is accumulating for incretin-based therapies as effective measure for preventing of cardio-metabolic complications [18].
In the last 18 months the MetS has received particular attention, since diabetes, obesity, and hypertension have been shown to be significantly associated with an increased risk for more severe forms of COVID-19 and related deaths [19]. The optimal management to address the multiple components of cardiometabolic risk during COVID-19 is still evolving. It has been suggested that a thoughtful approach to the management of cardiometabolic disorders would reduce inflammation, improve immune response, and prevent deterioration in case of SARS-Cov-2 infection [20]. The data gathered thus far could guide future management of patients with the MetS in order to reduce the risk of developing these complications [21].
This Special Issue aims to provide an update on the latest research in MetS, shedding light on emerging markers, unravelling potential molecular mechanisms, and highlighting innovative remedies to be utilized in concert with lifestyle modifications. We hope that the issue will assist readers in keeping abreast of the health challenges and their emerging solutions in the modern era of the COVID-19 pandemic. Our intention is to gather relevant knowledge under one umbrella as a resource for clinicians and for the benefit of patients with the MetS and its complications.

Author Contributions

The three authors have contributed equally to the present work. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Conflicts of Interest

The authors declare that this article has been written independently. APS is currently Vice President of Romanian National Diabetes Committee, and she has given lectures, received honoraria and research support, and participated in conferences, advisory boards, and clinical trials sponsored by many pharmaceutical companies including AstraZeneca, Boehringer Ingelheim, Medtronic, Eli Lilly, Merck, Novo Nordisk, Novartis, Roche Diagnostics, and Sanofi. MR is a full-time Professor of Internal Medicine at the University of Palermo, Italy, Editor in Chief of the International Journal of Molecular Sciences section Molecular Endocrinology and Metabolism, and currently Medical Director in Novo Nordisk Eastern Europe; he has given lectures, received honoraria and research support, and participated in conferences, advisory boards, and clinical trials sponsored by many pharmaceutical companies including Amgen, Astra Zeneca, Boehringer Ingelheim, Kowa, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Novartis, Roche Diagnostics, Sanofi, and Servier. None of the above-mentioned pharmaceutical companies had any role in this article, which has been written independently, without any financial or professional help, and reflects only the opinion of the authors, without any role of the industry.


  1. Reaven, G.M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988, 37, 1595–1607. [Google Scholar] [CrossRef]
  2. Kahn, R.; Buse, J.; Ferrannini, E.; Stern, M. The Metabolic Syndrome: Time for a Critical Appraisal: Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005, 28, 2289–2304. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Einhorn, D.; Reaven, G.M.; Cobin, R.H.; Ford, E.; Ganda, O.P.; Handelsman, Y.; Hellman, R.; Jellinger, P.S.; Kendall, D.; Krauss, R.M.; et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr. Pr. 2003, 9, 237–252. [Google Scholar]
  4. Ramzan, F.; Vickers, M.; Mithen, R. Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review. Int. J. Mol. Sci. 2021, 22, 5047. [Google Scholar] [CrossRef] [PubMed]
  5. Abate, N.; Sallam, H.S.; Rizzo, M.; Nikolic, D.; Obradovic, M.; Bjelogrlic, P.; Isenovic, E.R. Resistin: An inflamma-tory cytokine. Role in cardiovascular diseases, diabetes and the metabolic syndrome. Curr. Pharm. Des. 2014, 20, 4961–4969. [Google Scholar] [CrossRef]
  6. Rizvi, A.A. Cytokine biomarkers, endothelial inflammation, and atherosclerosis in the metabolic syn-drome: Emerging concepts. Am. J. Med. Sci. 2009, 338, 310–318. [Google Scholar] [CrossRef]
  7. Berneis, K.K.; Krauss, R.M. Metabolic origins and clinical significance of LDL heterogeneity. J. Lipid Res. 2002, 43, 1363–1379. [Google Scholar] [CrossRef][Green Version]
  8. Rizzo, M.; Berneis, K. Who needs to care about small, dense low-density lipoproteins? Int. J. Clin. Pr. 2007, 61, 1949–1956. [Google Scholar] [CrossRef]
  9. Berneis, K.; Rizzo, M.; Hersberger, M.; Rini, G.B.; Di Fede, G.; Pepe, I.; Spinas, G.A.; Carmina, E. Atherogenic forms of dyslipidemia in women with polycystic ovary syndrome. Int. J. Clin. Pr. 2009, 63, 56–62. [Google Scholar] [CrossRef]
  10. Rizzo, M.; Pernice, V.; Frasheri, A.; Berneis, K. Atherogenic lipoprotein phenotype and LDL size and sub-classes in patients with peripheral arterial disease. Atherosclerosis 2008, 197, 237–241. [Google Scholar] [CrossRef]
  11. Rizzo, M.; Berneis, K.; Altinova, A.E.; Toruner, F.B.; Akturk, M.; Ayvaz, G.; Rini, G.B.; Spinas, G.A.; Arslan, M. Athero-genic lipoprotein phenotype and LDL size and subclasses in women with gestational diabetes. Diabet Med. 2008, 25, 1406–1411. [Google Scholar] [CrossRef] [PubMed]
  12. Goedecke, J.H.; Utzschneider, K.; Faulenbach, M.V.; Rizzo, M.; Berneis, K.; Spinas, G.A.; Dave, J.; Levitt, N.S.; Lambert, E.; Olsson, T.; et al. Ethnic differences in serum lipoproteins and their determinants in South African women. Metabolism 2010, 59, 1341–1350. [Google Scholar] [CrossRef] [PubMed]
  13. Rizzo, M.; Spinas, G.A.; Cesur, M.; Ozbalkan, Z.; Rini, G.B.; Berneis, K. Atherogenic lipoprotein phenotype and LDL size and subclasses in drug-naïve patients with early rheumatoid arthritis. Atherosclerosis 2009, 207, 502–506. [Google Scholar] [CrossRef] [PubMed]
  14. Corrado, E.; Rizzo, M.; Coppola, G.; Muratori, I.; Carella, M.; Novo, S. Endothelial dysfunction and carotid le-sions are strong predictors of clinical events in patients with early stages of atherosclerosis: A 24-month follow-up study. Coron. Artery. Dis. 2008, 19, 139–144. [Google Scholar] [CrossRef]
  15. Rizzo, M.; Rizvi, A.A.; Patti, A.M.; Nikolic, D.; Giglio, R.V.; Castellino, G.; Li Volti, G.; Caprio, M.; Montalto, G.; Provenzano, V.; et al. Liraglutide improves metabolic parameters and carotid inti-ma-media thickness in diabetic patients with the metabolic syndrome: An 18-month prospective study. Cardiovasc. Diabetol. 2016, 15, 162. [Google Scholar] [CrossRef][Green Version]
  16. Patti, A.M.; Nikolic, D.; Magan-Fernandez, A.; Giglio, R.V.; Castellino, G.; Chianetta, R.; Citarrella, R.; Corrado, E.; Provenzano, F.; Provenzano, V.; et al. Exenatide once-weekly improves metabolic parameters, endothelial dysfunction and carotid intima-media thickness in patients with type-2 diabe-tes: An 8-month prospective study. Diabetes Res. Clin. Pr. 2019, 149, 163–169. [Google Scholar] [CrossRef]
  17. Nikolic, D.; Giglio, R.V.; Rizvi, A.A.; Patti, A.M.; Montalto, G.; Maranta, F.; Cianflone, D.; Stoian, A.P.; Rizzo, M. Lirag-lutide reduces carotid intima-media thickness by reducing small dense low-density lipoproteins in a re-al-world setting of patients with type 2 diabetes: A novel anti-atherogenic effect. Diabetes 2021, 12, 261–274. [Google Scholar]
  18. Nauck, M.A.; Quast, D.R.; Wefers, J.; Pfeiffer, A.F. The Evolving Story of Incretins (GIP and GLP-1) in Metabolic and Cardiovascular Disease: A Pathophysiological Update. Diabetes Obes. Metab. 2021. [Google Scholar] [CrossRef]
  19. Ceriello, A.; Stoian, A.P.; Rizzo, M. COVID-19 and diabetes management: What should be considered? Diabetes Res. Clin. Pr. 2020, 163, 108151. [Google Scholar] [CrossRef]
  20. Tessier, C.M.; Kokkinos, A.; Mingrone, G.; Koliaki, C.; Zierath, J.R.; Mantzoros, C.S. COVID-19 editorial: Mechanistic links and therapeutic challenges for metabolic diseases one year into the COVID-19 pandemic. Metabolism 2021, 119, 154769. [Google Scholar] [CrossRef]
  21. Stoian, A.P.; Banerjee, Y.; Rizvi, A.A.; Rizzo, M. Diabetes and the COVID-19 Pandemic: How Insights from Re-cent Experience Might Guide Future Management. Metab Syndr. Relat. Disord. 2020, 18, 173–175. [Google Scholar] [CrossRef] [PubMed]
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Rizvi, A.A.; Stoian, A.P.; Rizzo, M. Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies. Int. J. Mol. Sci. 2021, 22, 10038.

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Rizvi AA, Stoian AP, Rizzo M. Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies. International Journal of Molecular Sciences. 2021; 22(18):10038.

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Rizvi, Ali Abbas, Anca Pantea Stoian, and Manfredi Rizzo. 2021. "Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies" International Journal of Molecular Sciences 22, no. 18: 10038.

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