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New Advances in Metabolic Syndrome

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 39291

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Special Issue Editors

Prof. Dr. Manfredi Rizzo

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Guest Editor

Department of Internal Medicine and Medical Specialties (DIMIS), Università degli Studi di Palermo UNIPA, 90100 Palermo, Italy
Interests: cardiovascular risk; lipids; diabetes; prevention; therapy; metabolic syndrome; metabolism; lipoproteins; incretins; nutraceuticals
Special Issues, Collections and Topics in MDPI journals

Dr. Ali Abbas Rizvi

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Guest Editor

Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, GA, USA
Interests: metabolic syndrome; diabetes; cardiovascular and type 2 diabetes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The metabolic syndrome (MetS) consists of a cluster of metabolic abnormalities including central obesity, insulin resistance, glucose intolerance, hypertension, and atherogenic dyslipidemia. It is rapidly emerging as a global health problem that increases the risk of developing type 2 diabetes and cardiovascular diseases. Early recognition using clinical parameters and inflammatory markers is imperative in order to reduce morbidity and possibly mortality, too, attributable to the syndrome. A number of susceptibility genes have been identified that are thought to play a role in the genetic etiology of MetS, thus paving the way to new molecular insights. Knowledge of the etiopathogenic pathways could facilitate novel therapeutic approaches to treating MetS. The link between MetS and diabetes and its complications, cardiovascular disease, and nephropathy is a newly developing paradigm with the central point being early atherosclerosis and endovascular inflammation. This Special Issue aims to provide an update on the latest research in MetS, shedding light on emerging markers unravelling molecular mechanisms and innovative remedies to be utilized in concert.

Prof. Dr. Manfredi Rizzo
Prof. Dr. Ali A. Rizvi
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

metabolic syndrome
risk factors
diabetes
cardiovascular disease
atherosclerosis
dyslipidemia
hypertension
obesity
insulin resistance
renal kidney disease
inflammation markers
molecular mechanism
oxidative stress
therapy

Published Papers (11 papers)

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Research

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29 pages, 9354 KiB

Open AccessArticle

Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients

by Katherine A. Glass, Arnaud Germain, Yuhsin V. Huang and Maureen R. Hanson

Int. J. Mol. Sci. 2023, 24(4), 3685; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043685 - 12 Feb 2023

Cited by 5 | Viewed by 15605

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown etiology or effective treatments. Post-exertional malaise (PEM) is a key symptom that distinguishes ME/CFS patients. Investigating changes in the urine metabolome between ME/CFS patients and healthy subjects following exertion may help us understand PEM. The aim of this pilot study was to comprehensively characterize the urine metabolomes of eight female healthy sedentary control subjects and ten female ME/CFS patients in response to a maximal cardiopulmonary exercise test (CPET). Each subject provided urine samples at baseline and 24 h post-exercise. A total of 1403 metabolites were detected via LC-MS/MS by Metabolon^® including amino acids, carbohydrates, lipids, nucleotides, cofactors and vitamins, xenobiotics, and unknown compounds. Using a linear mixed effects model, pathway enrichment analysis, topology analysis, and correlations between urine and plasma metabolite levels, significant differences were discovered between controls and ME/CFS patients in many lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, SAM, and taurine; leucine, isoleucine, and valine; polyamine; tryptophan; and urea cycle, arginine and proline). Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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0 pages, 2725 KiB

Open AccessArticle

Meta-Analysis and Multivariate GWAS Analyses in 80,950 Individuals of African Ancestry Identify Novel Variants Associated with Blood Pressure Traits

by Brenda Udosen, Opeyemi Soremekun, Abram Kamiza, Tafadzwa Machipisa, Cisse Cheickna, Olaposi Omotuyi, Mahmoud Soliman, Mamadou Wélé, Oyekanmi Nashiru, Tinashe Chikowore and Segun Fatumo

Int. J. Mol. Sci. 2023, 24(3), 2164; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032164 - 21 Jan 2023

Cited by 2 | Viewed by 2589 | Correction

Abstract

High blood pressure (HBP) has been implicated as a major risk factor for cardiovascular diseases in several populations, including individuals of African ancestry. Despite the elevated burden of HBP-induced cardiovascular diseases in Africa and other populations of African descent, limited genetic studies have been carried out to explore the genetic mechanism driving this phenomenon. We performed genome-wide association univariate and multivariate analyses of both systolic (SBP) and diastolic blood pressure (DBP) traits in 80,950 individuals of African ancestry. We used summary statistics data from six independent cohorts, including the African Partnership for Chronic Disease Research (APCDR), the UK Biobank, and the Million Veteran Program (MVP). FUMA was used to annotate, prioritize, visualize, and interpret our findings to gain a better understanding of the molecular mechanism(s) underlying the genetics of BP traits. Finally, we undertook a Bayesian fine-mapping analysis to identify potential causal variants. Our meta-analysis identified 10 independent variants associated with SBP and 9 with DBP traits. Whilst our multivariate GWAS method identified 21 independent signals, 18 of these SNPs have been previously identified. SBP was linked to gene sets involved in biological processes such as synapse assembly and cell–cell adhesion via plasma membrane adhesion. Of the 19 independent SNPs identified in the BP meta-analysis, only 11 variants had posterior probability (PP) of > 50%, including one novel variant: rs562545 (MOBP, PP = 77%). To facilitate further research and fine-mapping of high-risk loci/variants in highly susceptible groups for cardiovascular disease and other related traits, large-scale genomic datasets are needed. Our findings highlight the importance of including ancestrally diverse populations in large GWASs and the need for diversity in genetic research. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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11 pages, 574 KiB

Open AccessArticle

Association between Fasting and Postprandial Levels of Liver Enzymes with Metabolic Syndrome and Suspected Prediabetes in Prepubertal Children

by Katarzyna Bergmann, Anna Stefanska, Magdalena Krintus, Lukasz Szternel, Mauro Panteghini and Grazyna Sypniewska

Int. J. Mol. Sci. 2023, 24(2), 1090; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021090 - 06 Jan 2023

Viewed by 1409

Abstract

Elevated liver enzyme activity may be associated with metabolic syndrome (MetS); however, it is not included in the MetS definition for children. Postprandial changes in the levels of biochemistry tests are related to manifestations of metabolic abnormalities. We assessed the association between fasting and postprandial liver enzymes levels with MetS and elevated hemoglobin A1c (HbA1c) in children aged 9–11. The study included 51 girls and 48 boys, all presumably healthy. In all participants’ anthropometric indices, fasting glucose, insulin, lipid profile and HbA1c were measured. Enzymes, including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), were assayed in fasting and postprandial states. Individuals were divided into subgroups: with (MetS(+): n = 26); without MetS (MetS(−): n = 73); with HbA1c levels ≤ 5.3% (n = 39); and ≥5.7% (n = 11). Elevated fasting GGT levels were found in 23% of MetS(+) children and rarely in MetS(−) children; increased postprandial GGT was noted in 35% of MetS(+) individuals. Postprandial GGT changes tend to predict MetS (OR = 1.16; p = 0.092). Increased fasting ALT was found rarely in MetS(+) children, but did not occur in MetS(−) children. HbA1c ≥ 5.7% occurred rarely and neither fasting ALT nor GGT were related to elevated HbA1c. However, postprandial change of ALT was a good positive predictor of increased HbA1c (OR = 1.33; p = 0.021). Postprandial GGT performs better as an indicator of metabolic syndrome occurrence, and instead postprandial ALT may predict prediabetes in prepubertal children. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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11 pages, 1701 KiB

Open AccessArticle

Hepatic Oleate Regulates Insulin-like Growth Factor-Binding Protein 1 Partially through the mTORC1-FGF21 Axis during High-Carbohydrate Feeding

by Lucas M. O’Neill, Yar Xin Phang, Zhaojin Liu, Sarah A. Lewis, Ahmed Aljohani, Ayren McGahee, Gina Wade, Mugagga Kalyesubula, Judith Simcox and James M. Ntambi

Int. J. Mol. Sci. 2022, 23(23), 14671; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314671 - 24 Nov 2022

Cited by 2 | Viewed by 1701

Abstract

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the rate-liming step of monounsaturated fatty acid biosynthesis and is a key regulator of systemic glucose metabolism. Mice harboring either a global (GKO) or liver-specific deletion (LKO) of Scd1 display enhanced insulin signaling and whole-body glucose uptake. Additionally, GKO and LKO mice are protected from high-carbohydrate diet-induced obesity. Given that high-carbohydrate diets can lead to chronic metabolic diseases such as obesity, diabetes, and hepatic steatosis, it is critical to understand how Scd1 deficiency confers metabolically beneficial phenotypes. Here we show that insulin-like growth factor-binding protein 1 (IGFBP1), a hepatokine that has been reported to enhance insulin signaling, is significantly elevated in the liver and plasma of GKO and LKO mice fed a low-fat high-carbohydrate diet. We also observed that the expression of hepatic Igfbp1 is regulated by oleic acid (18:1n9), a product of SCD1, through the mTORC1-FGF21 axis both in vivo and in vitro. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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15 pages, 2042 KiB

Open AccessArticle

Study of Hypoglycemic Activity of Novel 9-N-alkyltetrahydroberberine Derivatives

by Mikhail V. Khvostov, Elizaveta D. Gladkova, Sergey A. Borisov, Marina S. Fedotova, Nataliya A. Zhukova, Mariya K. Marenina, Yuliya V. Meshkova, Olga A. Luzina, Tatiana G. Tolstikova and Nariman F. Salakhutdinov

Int. J. Mol. Sci. 2022, 23(22), 14186; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214186 - 16 Nov 2022

Cited by 1 | Viewed by 1549

Abstract

Novel 9-N-alkyltetrahydroberberine derivatives were synthesized, among which, based on the results of OGTT, one compound containing the longest aliphatic substituent was selected for study in mice C57BL/6^Ay, which demonstrate obesity, impaired glucose tolerance, and concomitant liver non-alcoholic fatty disease. Administration of this substance at a dose of 15 mg/kg for four weeks improved the insulin sensitivity of mice, which resulted in a decrease in fasting glucose levels and improved the tolerance of mice to OGTT glucose loading. A decrease in the level of lactate in the blood and a decrease in the amount of glucokinase in the liver were also found. The introduction of compound 3c did not have a toxic effect on animals based on biochemical data, histological analysis, and measurements of general parameters such as body weight and feed intake. Thus, the 9-N-heptyltetrahydroberberine derivative showed prominent hypoglycemic effects, which makes it promising to obtain and study other derivatives with longer substituents. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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11 pages, 1976 KiB

Open AccessArticle

Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice

by Wenhua Shao, Orgil Jargalsaikhan, Mayuko Ichimura-Shimizu, Qinyi Cai, Hirohisa Ogawa, Yuko Miyakami, Kengo Atsumi, Mitsuru Tomita, Mitsuko Sutoh, Shunji Toyohara, Ryoji Hokao, Yasusei Kudo, Takeshi Oya and Koichi Tsuneyama

Int. J. Mol. Sci. 2022, 23(19), 11923; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911923 - 07 Oct 2022

Cited by 1 | Viewed by 1888

Abstract

Male Tsumura-Suzuki Obese Diabetes (TSOD) mice, a spontaneous metabolic syndrome model, develop non-alcoholic steatohepatitis and liver tumors by feeding on a standard mouse diet. Nearly 70% of liver tumors express glutamine synthetase (GS), a marker of hepatocellular carcinoma. In contrast, approximately 30% are GS-negative without prominent nuclear or structural atypia. In this study, we examined the characteristics of the GS-negative tumors of TSOD mice. Twenty male TSOD mice were sacrificed at 40 weeks and a total of 21 tumors were analyzed by HE staining and immunostaining of GS, liver fatty acid-binding protein (L-FABP), serum amyloid A (SAA), and beta-catenin. With immunostaining for GS, six (29%) tumors were negative. Based on the histological and immunohistological characteristics, six GS-negative tumors were classified into several subtypes of human hepatocellular adenoma (HCA). One large tumor showed generally similar findings to inflammatory HCA, but contained small atypical foci with GS staining and partial nuclear beta-catenin expression suggesting malignant transformation. GS-negative tumors of TSOD mice contained features similar to various subtypes of HCA. Different HCA subtypes occurring in the same liver have been reported in humans; however, the diversity of patient backgrounds limits the ability to conduct a detailed, multifaceted analysis. TSOD mice may share similar mechanisms of HCA development as in humans. It is timely to review the pathogenesis of HCA from both genetic and environmental perspectives, and it is expected that TSOD mice will make further contributions in this regard. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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14 pages, 317 KiB

Open AccessArticle

Unravelling the Contribution of the rs7041 and rs4588 Polymorphisms of the GC Gene and Serum VDBP Levels for Developing Metabolic Syndrome in the Mexican Population

by Alberto Hidalgo-Bravo, Berenice Rivera-Paredez, Guadalupe León-Reyes, Nelly Patiño, Manuel Castillejos-López, Jorge Salmerón and Rafael Velázquez-Cruz

Int. J. Mol. Sci. 2022, 23(18), 10581; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810581 - 13 Sep 2022

Cited by 3 | Viewed by 1599

Abstract

Metabolic syndrome (MetS) is a multifactorial disorder integrated by a constellation of cardiovascular risk factors. The genetic and environmental determinants of MetS are not fully elucidated. This study investigated the association of two common single nucleotide polymorphisms (SNPs) on GC, rs7041 and rs4588, derived haplotypes, and serum vitamin D binding protein (VDBP) levels with the susceptibility to suffer MetS in Mexican adults. We included 1924 individuals; clinical and biochemical data were obtained through standard methods. Genotyping was performed through predesigned TaqMan assays. Logistic regression models were used to assess the associations of interest. Prevalence of MetS was 52.9% in the whole population, being more frequent in women. We observed that some association results differed between sexes. The GG genotype of the rs7041 was associated with increased odds of MetS in women. For the rs4588, the CA genotype had a protective effect against MetS in women. The haplotype GC2 was associated with reduced odds for MetS and some of its components in women. Our data suggest that VDBP serum levels were influenced by genotypes/haplotypes and this interplay seems to influence the risk of MetS. Our data provide reliable evidence regarding the association of GC polymorphisms with MetS risk in Mexican women. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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Review

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19 pages, 1620 KiB

Open AccessReview

Metabolic Syndrome as a Risk Factor for Alzheimer’s Disease: A Focus on Insulin Resistance

by Amaia Ezkurdia, María J. Ramírez and Maite Solas

Int. J. Mol. Sci. 2023, 24(5), 4354; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054354 - 22 Feb 2023

Cited by 18 | Viewed by 6375

Abstract

Alzheimer’s disease (AD) is the main type of dementia and is a disease with a profound socioeconomic burden due to the lack of effective treatment. In addition to genetics and environmental factors, AD is highly associated with metabolic syndrome, defined as the combination of hypertension, hyperlipidemia, obesity and type 2 diabetes mellitus (T2DM). Among these risk factors, the connection between AD and T2DM has been deeply studied. It has been suggested that the mechanism linking both conditions is insulin resistance. Insulin is an important hormone that regulates not only peripheral energy homeostasis but also brain functions, such as cognition. Insulin desensitization, therefore, could impact normal brain function increasing the risk of developing neurodegenerative disorders in later life. Paradoxically, it has been demonstrated that decreased neuronal insulin signalling can also have a protective role in aging and protein-aggregation-associated diseases, as is the case in AD. This controversy is fed by studies focused on neuronal insulin signalling. However, the role of insulin action on other brain cell types, such as astrocytes, is still unexplored. Therefore, it is worthwhile exploring the involvement of the astrocytic insulin receptor in cognition, as well as in the onset and/or development of AD. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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11 pages, 686 KiB

Open AccessReview

Relationships between Diabetes and the Intestinal Microbial Population

by Stephen C. Bondy

Int. J. Mol. Sci. 2023, 24(1), 566; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010566 - 29 Dec 2022

Cited by 1 | Viewed by 2017

Abstract

Diabetes is a metabolic disorder characterized by lower responsiveness of tissues to insulin and consequent large variations in circulating levels of glucose. This fluctuation has harmful effects as both hyperglycemia and hypoglycemia can be very injurious. The causes of diabetes are varied but the consequences are rather uniform. Dietary factors are important especially in adult onset type 2 diabetes (T2D) while type 1 diabetes (T1D) is characterized by having a stronger heritable component and involving autoimmune attach on pancreatic beta cells. This review is focused on the relation of the bacterial components found within the intestine, to the establishment and maintenance of diabetes. The precise composition of the gut microbiome is increasingly recognized as a factor in organismic health and its interaction with a variety of disease states has been described. This is especially marked in the case of diabetes since the nature of the diet is an important factor in establishing both the microbiome and the incidence of diabetes. The bidirectional nature of this relationship is discussed. The effects of disease that lead to altered microbiomal composition together with aberrant metabolic changes are also included. Emphasis is given to the important role of short chain fatty acids (SCFAs) as mediators of the microbiome-diabetes relation. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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16 pages, 1226 KiB

Open AccessReview

Gut Microbiome Changes in Gestational Diabetes

by Ruxandra Florentina Ionescu, Robert Mihai Enache, Sanda Maria Cretoiu and Bogdan Severus Gaspar

Int. J. Mol. Sci. 2022, 23(21), 12839; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112839 - 25 Oct 2022

Cited by 11 | Viewed by 3145

Abstract

Gestational diabetes mellitus (GDM), one of the most common endocrine pathologies during pregnancy, is defined as any degree of glucose intolerance with onset or first discovery in the perinatal period. Physiological changes that occur in pregnant women can lead to inflammation, which promotes insulin resistance. In the general context of worldwide increasing obesity in young females of reproductive age, GDM follows the same ascending trend. Changes in the intestinal microbiome play a decisive role in obesity and the development of insulin resistance and chronic inflammation, especially in patients with type 2 diabetes mellitus (T2D). To date, various studies have also associated intestinal dysbiosis with metabolic changes in women with GDM. Although host metabolism in women with GDM has not been fully elucidated, it is of particular importance to analyze the available data and to discuss the actual knowledge regarding microbiome changes with potential impact on the health of pregnant women and newborns. We analyzed peer-reviewed journal articles available in online databases in order to summarize the most recent findings regarding how variations in diet and metabolic status of GDM patients can contribute to alteration of the gut microbiome, in the same way that changes of the gut microbiota can lead to GDM. The most frequently observed alteration in the microbiome of patients with GDM was either an increase of the Firmicutes phylum, respectively, or a decrease of the Bacteroidetes and Actinobacteria phyla. Gut dysbiosis was still present postpartum and can impact the development of the newborn, as shown in several studies. In the evolution of GDM, probiotic supplementation and regular physical activity have the strongest evidence of proper blood glucose control, favoring fetal development and a healthy outcome for the postpartum period. The current review aims to summarize and discuss the most recent findings regarding the correlation between GDM and dysbiosis, and current and future methods for prevention and treatment (lifestyle changes, pre- and probiotics administration). To conclude, by highlighting the role of the gut microbiota, one can change perspectives about the development and progression of GDM and open up new avenues for the development of innovative therapeutic targets in this disease. Full article

(This article belongs to the Special Issue New Advances in Metabolic Syndrome)

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