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Diabetes: Molecular Mechanisms

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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 14110

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Dr. Maurizio Delvecchio

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Department of Metabolic and Genetic Diseases, Giovanni XXIII Children’s Hospital, 70126 Bari, Italy
Interests: neonatal diabetes mellitus; type 1 diabetes; celiac disease; thyroid disorders; insulin; Wolfram syndrome; Prader Villino syndrome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Diabetes mellitus is a heterogeneous group of disorders characterized by chronic hyperglycemia. Genetic background plays a role in the basis of the etiology of hyperglycemia, with a wide spectrum between type 1 and type 2 diabetes. In other rare forms, such as monogenic diabetes, mitochondrial diabetes, and diabetes associated with rare syndromes, genetics play a pivotal role.

Genetics do not provide any issue in the clinical management or primary prevention of type 1 and type 2 diabetes, but they may allow researchers to design intervention trials. Genetic testing may unravel individual susceptibilities and drive the choice to reduce risks by applying medical surveillance, lifestyle modficiations, or even drug therapy thanks to precision medicine.

This Special Issue focuses on high-quality research papers that address genetic issues in every type of diabetes mellitus. This Special Issue also welcomes papers about omics science or other kinds of molecular studies on this disorder. Contributions from a wide range of professions are welcome. Original research papers and state-of-the-art reviews will be accepted.

Dr. Maurizio Delvecchio
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

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Keywords

diabetes mellitus
MODY
monogenic diabetes
mitochondrial diabetes
neonatal diabetes
syndromic diabetes
pharmacogenomics
genetics
prevention
genetic etiology
precision medicine
omics sciences

Published Papers (7 papers)

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Research

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16 pages, 7147 KiB

Open AccessArticle

Sleeve Gastrectomy Improves Hepatic Glucose Metabolism by Downregulating FBXO2 and Activating the PI3K-AKT Pathway

by Ningyuan Chen, Ruican Cao, Zhao Zhang, Sai Zhou and Sanyuan Hu

Int. J. Mol. Sci. 2023, 24(6), 5544; https://doi.org/10.3390/ijms24065544 - 14 Mar 2023

Cited by 2 | Viewed by 1615

Abstract

Type 2 diabetes mellitus (T2DM), a chronic metabolic disease, is a public health concern that seriously endangers human health. Sleeve gastrectomy (SG) can relieve T2DM by improving glucose homeostasis and enhancing insulin sensitivity. However, its specific underlying mechanism remains elusive. SG and sham surgery were performed on mice fed a high-fat diet (HFD) for 16 weeks. Lipid metabolism was evaluated via histology and serum lipid analysis. Glucose metabolism was evaluated using the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Compared with the sham group, the SG group displayed a reduction in liver lipid accumulation and glucose intolerance, and western blot analysis revealed that the AMPK and PI3K-AKT pathways were activated. Furthermore, transcription and translation levels of FBXO2 were reduced after SG. After liver-specific overexpression of FBXO2, the improvement in glucose metabolism observed following SG was blunted; however, the remission of fatty liver was not influenced by the over expression of FBXO2. Our study explores the mechanism of SG in relieving T2DM, indicating that FBXO2 is a noninvasive therapeutic target that warrants further investigation. Full article

(This article belongs to the Special Issue Diabetes: Molecular Mechanisms)

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7 pages, 404 KiB

Open AccessCommunication

“Pesto” Mutation: Phenotypic and Genotypic Characteristics of Eight GCK/MODY Ligurian Patients

by Alessandro Salina, Marta Bassi, Concetta Aloi, Marina Francesca Strati, Renata Bocciardi, Giuseppe d’Annunzio, Mohamad Maghnie and Nicola Minuto

Int. J. Mol. Sci. 2023, 24(4), 4034; https://doi.org/10.3390/ijms24044034 - 17 Feb 2023

Viewed by 1301

Abstract

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes mellitus (DM) that accounts for around 2–5% of all types of diabetes. Autosomal dominant inheritance in pathogenic variations of 14 genes related to β-cell functions can lead to monogenic types of diabetes. In Italy, GCK/MODY is the most frequent form and it is caused by mutations of the glucokinase (GCK). Patients with GCK/MODY usually have stable mild fasting hyperglycaemia with mildly elevated HbA1c levels and rarely need pharmacological treatment. Molecular analysis of the GCK coding exons was carried out by Sanger sequencing in eight Italian patients. All the probands were found to be heterozygous carriers of a pathogenic gross insertion/deletion c.1279_1358delinsTTACA; p.Ser426_Ala454delinsLeuGln. It was previously described for the first time by our group in a large cohort of Italian GCK/MODY patients. The higher levels of HbA1c (6.57% vs. 6.1%), and the higher percentage of patients requiring insulin therapy (25% vs. 2%) compared to the previously studied Italian patients with GCK/MODY, suggest that the mutation discovered could be responsible for a clinically worse form of GCK/MODY. Moreover, as all the patients carrying this variant share an origin from the same geographic area (Liguria), we postulate a possible founder effect and we propose to name it the “pesto” mutation. Full article

(This article belongs to the Special Issue Diabetes: Molecular Mechanisms)

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29 pages, 6190 KiB

Open AccessArticle

Effect of Epstein–Barr Virus Infection on Selected Immunological Parameters in Children with Type 1 Diabetes

by Maria Klatka, Izabela Rysz, Anna Hymos, Agnieszka Polak, Paulina Mertowska, Sebastian Mertowski, Konrad Smolak and Ewelina Grywalska

Int. J. Mol. Sci. 2023, 24(3), 2392; https://doi.org/10.3390/ijms24032392 - 25 Jan 2023

Cited by 1 | Viewed by 1746

Abstract

Diabetes mellitus is a group of metabolic disorders with different etiologies, pathogeneses and clinical pictures, characterized by chronic hyperglycemia due to abnormal insulin secretion or action. Type 1 diabetes mellitus is the most common type of diabetes mellitus in children and adolescents, accounting for about 90% of diabetes in the population under the age of 18. The etiopathogenesis of type 1 diabetes is multifactorial. The disease occurs as a result of the interaction of three factors: genetic predisposition, environmental factors and the immune response. Research in recent years has focused on the involvement of Epstein–Barr virus (EBV) in the pathogenesis of type I diabetes. The goals of treating type 1 diabetes include maintaining blood-glucose, fructosamine and glycated hemoglobin (HbA1c) levels; therefore, the main purpose of this study was to evaluate the effect of EBV infection on the activation of selected immune cells, fructosamine levels and HbA1c levels in children with type I diabetes. Based on our study, we found a lower percentage of CD8+ T lymphocytes with expression of the CD69 molecule in patients with anti-VCA antibodies in the IgG class, and a lower percentage of CD8+ T lymphocytes with expression of the CD25+ molecule in patients with anti-EBNA-1 antibodies in the IgG class, which may indicate limited control of the immune system during EBV infection in patients. There was a lower percentage of CD3+CD4+ T lymphocytes secreting IL-4 in the study group, indicating that a deficiency in IL-4 production may be related to the development of type 1 diabetes. There was an increase in the percentage of CD4+CD3+IL-10 lymphocytes in the study group with anti-VCA antibodies present in the IgG class and anti-EBNA-1 antibodies in the IgG class compared to the patients without antibodies. In addition, there was a significant increase in fructosamine levels and higher glycated hemoglobin levels in the study group with antibodies to EBV antigens. In addition, an increase in the percentage of T lymphocytes with a CD4+CD3+IL-17+ phenotype in the patients with anti-VCA IgG antibodies was confirmed, and higher HbA1c levels may suggest that EBV infection is accompanied by an increase in IL-17 secretion. Full article

(This article belongs to the Special Issue Diabetes: Molecular Mechanisms)

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16 pages, 1761 KiB

Open AccessArticle

Diabetic Encephalopathy in a Preclinical Experimental Model of Type 1 Diabetes Mellitus: Observations in Adult Female Rat

by Eva Falvo, Silvia Giatti, Silvia Diviccaro, Lucia Cioffi, Monika Herian, Paola Brivio, Francesca Calabrese, Donatella Caruso and Roberto Cosimo Melcangi

Int. J. Mol. Sci. 2023, 24(2), 1196; https://doi.org/10.3390/ijms24021196 - 7 Jan 2023

Cited by 3 | Viewed by 1438

Abstract

Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk of cognitive deficits, dementia and Alzheimer’s disease, but the mechanisms are not fully explored. In the male animal models of DM, the development of cognitive impairment seems to be the result of the concomitance of different processes such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and aberrant synaptogenesis. However, even if diabetic encephalopathy shows some sex-dimorphic features, no observations in female rats have been so far reported on these aspects. Therefore, in an experimental model of type 1 DM (T1DM), we explored the impact of one month of pathology on memory abilities by the novel object recognition test and on neuroinflammation, synaptogenesis and mitochondrial functionality. Moreover, given that steroids are involved in memory and learning, we also analysed their levels and receptors. We reported that memory dysfunction can be associated with different features in the female hippocampus and cerebral cortex. Indeed, in the hippocampus, we observed aberrant synaptogenesis and neuroinflammation but not mitochondrial dysfunction and oxidative stress, possibly due to the results of locally increased levels of progesterone metabolites (i.e., dihydroprogesterone and allopregnanolone). These observations suggest specific brain-area effects of T1DM since different alterations are observed in the cerebral cortex. Full article

(This article belongs to the Special Issue Diabetes: Molecular Mechanisms)

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13 pages, 1269 KiB

Open AccessArticle

The Genetic Spectrum of Maturity-Onset Diabetes of the Young (MODY) in Qatar, a Population-Based Study

by Asma A. Elashi, Salman M. Toor, Ilhame Diboun, Yasser Al-Sarraj, Shahrad Taheri, Karsten Suhre, Abdul Badi Abou-Samra and Omar M. E. Albagha

Int. J. Mol. Sci. 2023, 24(1), 130; https://doi.org/10.3390/ijms24010130 - 21 Dec 2022

Cited by 2 | Viewed by 3037

Abstract

Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes mellitus. In this study, we estimated the prevalence and genetic spectrum of MODY in the Middle Eastern population of Qatar using whole-genome sequencing (WGS) of 14,364 subjects from the population-based Qatar biobank (QBB) cohort. We focused our investigations on 14 previously identified genes ascribed to the cause of MODY and two potentially novel MODY-causing genes, RFX6 and NKX6-1. Genetic variations within the 16 MODY-related genes were assessed for their pathogenicity to identify disease-causing mutations. Analysis of QBB phenotype data revealed 72 subjects (0.5%) with type 1 diabetes, 2915 subjects (20.3%) with type 2 diabetes and 11,377 (79.2%) without diabetes. We identified 22 mutations in 67 subjects that were previously reported in the Human Genetic Mutation Database (HGMD) as disease-causing (DM) or likely disease causing (DM?) for MODY. We also identified 28 potentially novel MODY-causing mutations, predicted to be among the top 1% most deleterious mutations in the human genome, which showed complete (100%) disease penetrance in 34 subjects. Overall, we estimated that MODY accounts for around 2.2–3.4% of diabetes patients in Qatar. This is the first population-based study to determine the genetic spectrum and estimate the prevalence of MODY in the Middle East. Further research to characterize the newly identified mutations is warranted. Full article

(This article belongs to the Special Issue Diabetes: Molecular Mechanisms)

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Review

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17 pages, 1342 KiB

Open AccessReview

The ABA/LANCL Hormone/Receptor System in the Control of Glycemia, of Cardiomyocyte Energy Metabolism, and in Neuroprotection: A New Ally in the Treatment of Diabetes Mellitus?

by Sonia Spinelli, Mirko Magnone, Lucrezia Guida, Laura Sturla and Elena Zocchi

Int. J. Mol. Sci. 2023, 24(2), 1199; https://doi.org/10.3390/ijms24021199 - 7 Jan 2023

Cited by 2 | Viewed by 2047

Abstract

Abscisic acid (ABA), long known as a plant stress hormone, is present and functionally active in organisms other than those pertaining to the land plant kingdom, including cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. The ancient, cross-kingdom role of this stress hormone allows ABA and its signaling pathway to control cell responses to environmental stimuli in diverse organisms such as marine sponges, higher plants, and humans. Recent advances in our knowledge about the physiological role of ABA and of its mammalian receptors in the control of energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells allow us to foresee therapeutic applications for ABA in the fields of pre-diabetes, diabetes, and cardio- and neuro-protection. Vegetal extracts titrated in their ABA content have shown both efficacy and tolerability in preliminary clinical studies. As the prevalence of glucose intolerance, diabetes, and cardiovascular and neurodegenerative diseases is steadily increasing in both industrialized and rapidly developing countries, new and cost-efficient therapeutics to combat these ailments are much needed to ensure disease-free aging for the current and future working generations. Full article

(This article belongs to the Special Issue Diabetes: Molecular Mechanisms)

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18 pages, 14921 KiB

Open AccessReview

Strategies for Therapeutic Amelioration of Aberrant Plasma Zn²⁺ Handling in Thrombotic Disease: Targeting Fatty Acid/Serum Albumin-Mediated Effects

by Spencer Regan-Smith, Remi Fritzen, Stephen J. Hierons, Ramzi A. Ajjan, Claudia A. Blindauer and Alan J. Stewart

Int. J. Mol. Sci. 2022, 23(18), 10302; https://doi.org/10.3390/ijms231810302 - 7 Sep 2022

Cited by 4 | Viewed by 2053

Abstract

The initiation, maintenance and regulation of blood coagulation is inexorably linked to the actions of Zn²⁺ in blood plasma. Zn²⁺ interacts with a variety of haemostatic proteins in the bloodstream including fibrinogen, histidine-rich glycoprotein (HRG) and high molecular weight kininogen (HMWK) to regulate haemostasis. The availability of Zn²⁺ to bind such proteins is controlled by human serum albumin (HSA), which binds 70–85% of plasma Zn²⁺ under basal conditions. HSA also binds and transports non-esterified fatty acids (NEFAs). Upon NEFA binding, there is a change in the structure of HSA which leads to a reduction in its affinity for Zn²⁺. This enables other plasma proteins to better compete for binding of Zn²⁺. In diseases where elevated plasma NEFA concentrations are a feature, such as obesity and diabetes, there is a concurrent increase in hypercoagulability. Evidence indicates that NEFA-induced perturbation of Zn²⁺-binding by HSA may contribute to the thrombotic complications frequently observed in these pathophysiological conditions. This review highlights potential interventions, both pharmaceutical and non-pharmaceutical that may be employed to combat this dysregulation. Lifestyle and dietary changes have been shown to reduce plasma NEFA concentrations. Furthermore, drugs that influence NEFA levels such as statins and fibrates may be useful in this context. In severely obese patients, more invasive therapies such as bariatric surgery may be useful. Finally, other potential treatments such as chelation therapies, use of cholesteryl transfer protein (CETP) inhibitors, lipase inhibitors, fatty acid inhibitors and other treatments are highlighted, which with additional research and appropriate clinical trials, could prove useful in the treatment and management of thrombotic disease through amelioration of plasma Zn²⁺ dysregulation in high-risk individuals. Full article

(This article belongs to the Special Issue Diabetes: Molecular Mechanisms)

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