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Recent Research on Diabetes Mellitus and Its Complications 2.0

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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 (30 May 2023) | Viewed by 15302

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Dr. Abdelkrim Hmadcha

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Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), Valencia, Spain
Interests: diabetes and diabetes complications; cancer; cardiovascular; peripheral artery disease (PAD); critical limb ischemia pathology (CLI); regulatory standards; clinical trials; advanced therapies; advanced therapies medicinal products (ATMP); stem cells; good manufacturing practice (GMP); quality assurance (QA); quality control (QC); molecular and cellular biology; epigenetics; microRNAs; exosomes
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Special Issue Information

Dear Colleagues,

The outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led not only to a global pandemic and a burden to public health but has also affected every aspect of our society and has undoubtedly changed the way science and medicine are conducted. Therefore, scientific and clinical investigations are ongoing at a dizzying speed and the rapidity of generating effective vaccines has been unprecedented. However, these scientific advances have also led to considerable shortcomings in other fields of research, such as diabetes. Continued support for basic research is more necessary than ever given the complexity associated with diabetes and its complications, and the growing number of people suffering from this common, chronic and costly disease.

Currently, treatment for diabetes consists of treating hyperglycemia by providing exogenous insulin and a supply of medication or by islet cell transplantation. However, the inability to achieve tight control of glucose regulation has motivated more efforts to develop other approaches to address diabetes and reduce the burden of existing diabetes complications. Moreover, the diabetes-based existence of a chronic inflammatory state, impaired immune response, impaired coagulation and other related complications could be among the underlying pathophysiological mechanisms contributing to the increased morbidity and mortality of COVID-19 patients with diabetes. Therefore, people at high risk for SARS-CoV2, such as those with diabetes, cardiovascular disease or immune disorders, should receive priority care and treatment if they contract COVID-19. In this regard, further molecular mechanistic approaches should be developed to better understand the existing correlation between COVID-19, diabetes and diabetes complications.

As Volume 1.0 of the Special Issue “Recent Research on Diabetes Mellitus and Its Complications ” (https://www.mdpi.com/journal/ijms/special_issues/Diabetes_Mellitus_Complications) was successful, we therefore reopen this topic for volume 2.0 in the International Journal of Molecular Sciences (https://www.mdpi.com/journal/ijms, ISSN 1422-0067, IF 5.924, JCR Category Q1). This second Special Issue aims to publish priority studies clarifying the recent advances in understanding the biochemical cellular and molecular mechanisms causing diabetes and diabetic complications.

The topic is broad, being focused on molecular biology, and is intended to cover basic research related, but not limited to:

Gene regulation (specific transcription factors, epigenetics, microRNAs and non-coding RNAs).
High-throughput “omics” (metabolomics, transcriptomics, and proteomics).
Islet development, β-cell dysfunction and allogenic islet and β-cell like transplantation.
Experimental animal models for diabetes and its complications.
Cardiovascular complications, diabetic retinopathy, nephropathy, neuropathy, non-alcoholic fatty liver disease and diabetic foot.
Oxidative stress, obesity, dyslipidemia, insulin resistance, inflammation and immunomodulation.
Stem cell and gene-based therapies, anti-diabetic drugs and small molecules.

Dr. Abdelkrim Hmadcha
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.

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

diabetes
diabetes complications
epigenetic
insulin resistance
metabolic pathways
glucose homeostasis
oxidative stress
β-cell

Published Papers (7 papers)

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Research

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18 pages, 3697 KiB

Open AccessArticle

NAD⁺ Precursors Reverse Experimental Diabetic Neuropathy in Mice

by Krish Chandrasekaran, Neda Najimi, Avinash R. Sagi, Sushuma Yarlagadda, Mohammad Salimian, Muhammed Ikbal Arvas, Ahmad F. Hedayat, Yanni Kevas, Anand Kadakia, Tibor Kristian and James W. Russell

Int. J. Mol. Sci. 2024, 25(2), 1102; https://doi.org/10.3390/ijms25021102 - 16 Jan 2024

Viewed by 1801

Abstract

Abnormal NAD⁺ signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD⁺ precursors could alleviate DPN symptoms through increasing the NAD⁺ levels and activating the sirtuin-1 (SIRT1) protein. To test this, we exposed cultured Dorsal Root Ganglion neurons (DRGs) to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which increased the levels of NAD⁺, the SIRT1 protein, and the deacetylation activity that is associated with increased neurite growth. A SIRT1 inhibitor blocked the neurite growth induced via NR or NMN. We then induced neuropathy in C57BL6 mice with streptozotocin (STZ) or a high fat diet (HFD) and administered NR or NMN for two months. Both the STZ and HFD mice developed neuropathy, which was reversed through the NR or NMN administration: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored. The NAD⁺ levels and SIRT1 activity were reduced in the DRGs from diabetic mice but were preserved with the NR or NMN treatment. We also tested the effect of NR or NMN administration in mice that overexpress the SIRT1 protein in neurons (nSIRT1 OE) and found no additional benefit from the addition of the drug. These findings suggest that supplementing with NAD+ precursors or activating SIRT1 may be a promising treatment for DPN. Full article

(This article belongs to the Special Issue Recent Research on Diabetes Mellitus and Its Complications 2.0)

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15 pages, 1960 KiB

Open AccessArticle

Postnatal Overfeeding during Lactation Induces Endothelial Dysfunction and Cardiac Insulin Resistance in Adult Rats

by Antonio Tejera-Muñoz, Lucía Guerra-Menéndez, Sara Amor, Daniel González-Hedström, Ángel Luis García-Villalón and Miriam Granado

Int. J. Mol. Sci. 2023, 24(19), 14443; https://doi.org/10.3390/ijms241914443 - 22 Sep 2023

Cited by 1 | Viewed by 941

Abstract

Early overnutrition is associated with cardiometabolic alterations in adulthood, likely attributed to reduced insulin sensitivity due to its crucial role in the cardiovascular system. This study aimed to assess the long-term effects of early overnutrition on the development of cardiovascular insulin resistance. An experimental childhood obesity model was established using male Sprague Dawley rats. Rats were organized into litters of 12 pups/mother (L12-Controls) or 3 pups/mother (L3-Overfed) at birth. After weaning, animals from L12 and L3 were housed three per cage and provided ad libitum access to food for 6 months. L3 rats exhibited elevated body weight, along with increased visceral, subcutaneous, and perivascular fat accumulation. However, heart weight at sacrifice was reduced in L3 rats. Furthermore, L3 rats displayed elevated serum levels of glucose, leptin, adiponectin, total lipids, and triglycerides compared to control rats. In the myocardium, overfed rats showed decreased IL-10 mRNA levels and alterations in contractility and heart rate in response to insulin. Similarly, aortic tissue exhibited modified gene expression of TNFα, iNOS, and IL-6. Additionally, L3 aortas exhibited endothelial dysfunction in response to acetylcholine, although insulin-induced relaxation remained unchanged compared to controls. At the molecular level, L3 rats displayed reduced Akt phosphorylation in response to insulin, both in myocardial and aortic tissues, whereas MAPK phosphorylation was elevated solely in the myocardium. Overfeeding during lactation in rats induces endothelial dysfunction and cardiac insulin resistance in adulthood, potentially contributing to the cardiovascular alterations observed in this experimental model. Full article

(This article belongs to the Special Issue Recent Research on Diabetes Mellitus and Its Complications 2.0)

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13 pages, 921 KiB

Open AccessArticle

Mitochondrial DNA Changes in Blood and Urine Display a Specific Signature in Relation to Inflammation in Normoalbuminuric Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients

by Ligia Petrica, Adrian Vlad, Florica Gadalean, Danina Mirela Muntean, Daliborca Vlad, Victor Dumitrascu, Flaviu Bob, Oana Milas, Anca Suteanu-Simulescu, Mihaela Glavan, Dragos Catalin Jianu, Sorin Ursoniu, Lavinia Balint, Maria Mogos-Stefan, Silvia Ienciu, Octavian Marius Cretu and Roxana Popescu

Int. J. Mol. Sci. 2023, 24(12), 9803; https://doi.org/10.3390/ijms24129803 - 6 Jun 2023

Cited by 4 | Viewed by 1557

Abstract

Mitochondrial dysfunction is an important mechanism contributing to the development and progression of diabetic kidney disease (DKD). Mitochondrial DNA (mtDNA) levels in blood and urine were evaluated in relation to podocyte injury and proximal tubule (PT) dysfunction, as well as to a specific inflammatory response in normoalbuminuric DKD. A total of 150 type 2 diabetes mellitus (DM) patients (52 normoalbuminuric, 48 microalbuminuric, and 50 macroalbuminuric ones, respectively) and 30 healthy controls were assessed concerning the urinary albumin/creatinine ratio (UACR), biomarkers of podocyte damage (synaptopodin and podocalyxin), PT dysfunction (kidney injury molecule-1 (KIM-1) and N-acetyl-β-(D)-glucosaminidase (NAG)), and inflammation (serum and urinary interleukins (IL-17A, IL-18, and IL-10)). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine via qRT-PCR. MtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies via analysis of the CYTB/B2M and ND2/B2M ratio. Multivariable regression analysis provided models in which serum mtDNA directly correlated with IL-10 and indirectly correlated with UACR, IL-17A, and KIM-1 (R² = 0.626; p < 0.0001). Urinary mtDNA directly correlated with UACR, podocalyxin, IL-18, and NAG, and negatively correlated with eGFR and IL-10 (R² = 0.631; p < 0.0001). Mitochondrial DNA changes in serum and urine display a specific signature in relation to inflammation both at the podocyte and tubular levels in normoalbuminuric type 2 DM patients. Full article

(This article belongs to the Special Issue Recent Research on Diabetes Mellitus and Its Complications 2.0)

16 pages, 12498 KiB

Open AccessArticle

Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection

by Rachel L. Washburn, Taylor Hibler, Gurvinder Kaur, Anna Sabu-Kurian, Alissa Landefeld and Jannette M. Dufour

Int. J. Mol. Sci. 2022, 23(24), 15894; https://doi.org/10.3390/ijms232415894 - 14 Dec 2022

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Abstract

An effective treatment and possible cure for type 1 diabetes is transplantation of pancreatic islets. Unfortunately, transplanted islets are rejected by the immune system with humoral-mediated responses being an important part of rejection. Sertoli cells (SC), an immune regulatory cell shown to survive as allografts long-term without immunosuppressants, have the potential to be used as a cell-based gene therapy vehicle to deliver endogenous insulin—a possible alternative to islets. Previously, we transduced a mouse SC line to produce human insulin. After transplantation into diabetic mice, these cells consistently produced low levels of insulin with graft survival of 75% at 50 days post-transplantation. The object of this study was to assess humoral immune regulation by these engineered SC. Both nontransduced and transduced SC survived exposure to human serum with complement in vitro. Analysis of allografts in vivo at 20 and 50 days post-transplantation revealed that despite IgG antibody detection, complement factor deposition was low and grafts survived through 50 days post-transplantation. Furthermore, the transduced SC secreted elevated levels of the complement inhibitor C1q binding protein. Overall, this suggests SC genetically engineered to express insulin maintain their ability to prevent complement-mediated killing. Since inhibiting complement-mediated rejection is important for graft survival, further studies of how SC modifies the immune response could be utilized to advance the use of genetically engineered SC or to prolong islet allograft survival to improve the treatment of diabetes. Full article

(This article belongs to the Special Issue Recent Research on Diabetes Mellitus and Its Complications 2.0)

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16 pages, 1822 KiB

Open AccessArticle

Vulgarin, a Sesquiterpene Lactone from Artemisia judaica, Improves the Antidiabetic Effectiveness of Glibenclamide in Streptozotocin-Induced Diabetic Rats via Modulation of PEPCK and G6Pase Genes Expression

by Hassan N. Althurwi, Gamal A. Soliman, Rehab F. Abdel-Rahman, Reham M. Abd-Elsalam, Hanan A. Ogaly, Mohammed H. Alqarni, Faisal F. Albaqami and Maged S. Abdel-Kader

Int. J. Mol. Sci. 2022, 23(24), 15856; https://doi.org/10.3390/ijms232415856 - 13 Dec 2022

Cited by 3 | Viewed by 1926

Abstract

The current investigation assessed the effect of the eudesmanolid, Vulgarin (VGN), obtained from Artemisia judaica (A. judaica), on the antidiabetic potential of glibenclamide (GLB) using streptozotocin (STZ) to induce diabetes. Seven groups of rats were used in the study; the first group received the vehicle and served as normal control. The diabetic rats of the second to the fifth groups were treated with the vehicle (negative control), GLB at 5 mg/kg (positive control), VGN at 10 mg/kg (VGN-10) and VGN at 20 mg/kg (VGN-20), respectively. The diabetic rats of the sixth and seventh groups were administered combinations of GLB plus VGN-10 and GLB plus VGN-20, respectively. The diabetic rats treated with GLB plus VGN-20 combination showed marked improvement in the fasting blood glucose (FBG), insulin and glycated hemoglobin (HbA1c), as well as the lipid profile, compared with those treated with GLB alone. Further, the pancreatic tissues of the diabetic rats that received the GLB+VGN-20 combination showed superior improvements in lipid peroxidation and antioxidant parameters than those of GLB monotherapy. The insulin content of the β-cells was restored in all treatments, while the levels of glucagon and somatostatin of the α- and δ-endocrine cells were reduced in the pancreatic islets. In addition, the concurrent administration of GLB+VGN-20 was the most effective in restoring PEPCK and G6Pase mRNA expression in the liver. In conclusion, the results demonstrated that the GLB+VGN-20 combination led to greater glycemic improvement in diabetic rats compared with GLB monotherapy through its antioxidant effect and capability to modulate PEPCK and G6Pase gene expression in their livers. Full article

(This article belongs to the Special Issue Recent Research on Diabetes Mellitus and Its Complications 2.0)

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Review

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23 pages, 2314 KiB

Open AccessReview

Insight into the Molecular Mechanism of Diabetic Kidney Disease and the Role of Metformin in Its Pathogenesis

by Marcin Kleibert, Przemysław Zygmunciak, Klaudia Łakomska, Klaudia Mila, Wojciech Zgliczyński and Beata Mrozikiewicz-Rakowska

Int. J. Mol. Sci. 2023, 24(17), 13038; https://doi.org/10.3390/ijms241713038 - 22 Aug 2023

Cited by 3 | Viewed by 2255

Abstract

Diabetic kidney disease (DKD) is one of the leading causes of death among patients diagnosed with diabetes mellitus. Despite the growing knowledge about the pathogenesis of DKD, we still do not have effective direct pharmacotherapy. Accurate blood sugar control is essential in slowing down DKD. It seems that metformin has a positive impact on kidneys and this effect is not only mediated by its hypoglycemic action, but also by direct molecular regulation of pathways involved in DKD. The molecular mechanism of DKD is complex and we can distinguish polyol, hexosamine, PKC, and AGE pathways which play key roles in the development and progression of this disease. Each of these pathways is overactivated in a hyperglycemic environment and it seems that most of them may be regulated by metformin. In this article, we summarize the knowledge about DKD pathogenesis and the potential mechanism of the nephroprotective effect of metformin. Additionally, we describe the impact of metformin on glomerular endothelial cells and podocytes, which are harmed in DKD. Full article

(This article belongs to the Special Issue Recent Research on Diabetes Mellitus and Its Complications 2.0)

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13 pages, 292 KiB

Open AccessReview

Influence of Gender in Diabetes Mellitus and Its Complication

by Tiziana Ciarambino, Pietro Crispino, Gaetano Leto, Erika Mastrolorenzo, Ombretta Para and Mauro Giordano

Int. J. Mol. Sci. 2022, 23(16), 8850; https://doi.org/10.3390/ijms23168850 - 9 Aug 2022

Cited by 31 | Viewed by 4518

Abstract

In medicine, there is growing evidence that gender differences are important and lead to variations in the pathophysiology and treatment of many diseases with traits that appear to be particularly relevant in influencing the outcomes of many morbid forms. Today, the inclusion of gender in biomedical research, to improve the scientific quality and scientific relevance of knowledge, of technology is an increasingly present element precisely due to the practical implications that derive from it. Gender differences describe the biological variability between women and men, which is, in turn, related to differences in the information contained in sex chromosomes, the specific gene expression of autosomes linked to sex, the different number and quality of sex hormones, and their different effects on systems and organs, without neglecting the fact that each of the sexes has different target organs on which these hormones act. Additionally, both genders undergo metabolic changes throughout their lives, and this is especially true for women who show more dramatic changes due to their role in reproduction. Gender differences are not only the result of our genetic makeup but are also mixed with socio-cultural habits, behaviors, and lifestyles, differences between women and men, exposure to specific environmental influences, different food and lifestyle styles or stress, or different attitude in compliance with treatments and disease prevention campaigns. Gender differences also affect behavior throughout life, and physical changes can have implications for lifestyle, social roles, and mental health. Therefore, determinism and therapeutic outcome in chronic diseases are influenced by a complex combination of biological and environmental factors, not forgetting that there are many interactions of social and biological factors in women and men. This review will address the role of gender differences in the management of various forms of diabetes and its complications considering the different biological functions of hormones, the difference in body composition, physiological differences in glucose and fat metabolism, also considering the role of the microbiota. intestinal, as well as the description of gestational diabetes linked to possible pathophysiological events typical of reproduction. Full article

(This article belongs to the Special Issue Recent Research on Diabetes Mellitus and Its Complications 2.0)

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