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Molecular Mechanism and Treatment of Diabetes Mellitus and Its Complications
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Molecular Mechanism and Treatment of Diabetes Mellitus and Its Complications

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: 20 September 2025 | Viewed by 5733

Special Issue Editor

Dr. Bernd Stratmann

E-Mail Website
Guest Editor
Herz- and Diabeteszentrum NRW, Diabeteszentrum, Ruhr Universität Bochum, 32545 Bad Oeynhausen, Germany
Interests: metabolic cardiomyopathy; diastolic dysfunction; diabetic late complications; advanced glycation endproducts

Special Issue Information

Dear Colleagues,

Much research has been carrried out to understand diabetes and its associated late complications. Nevertheless, day by day, we gain more information on how diabetes develops, progresses and, finally, in some patients earlier than in others, leads to increased multimorbidity and mortality.

As the Guest Editor of this Special Issue of IJMS, I am pleased to announce that we now have the chance to expand our knowledge on how diabetes develops in ways far removed from the proposed lifestyle-only hypothesis; thus; submissions including genetic analyses and cohort screenings are welcome for this Special Issue, including those regarding all types of diabetes including MODY. Those asking what makes type 1 diabetes a LADA and why it appears late are also welcome. Other relevant topics for this Special Issue include molecular mechanisms of new treatment options regarding type 1 or type 2 diabetes connecting the pancreas, liver, gut and kidney. In addition, we are interested in late complications and their associated mechanisms, paying special attention to micro- and macrovascular combinations like cardio-renal syndrome, polyneuropathy and cardiac autonomic neuropathy. The field in diabetes is widespread, so the range of topics of interest for this Special Issue is too.

Feel free to submit review articles as well as original work. Thank you for considering publishing your work with IJMS. Suitable topics include, but are not limited to: basic research, genetics, metabolomics and clinical research with biomolecular experiments.

Dr. Bernd Stratmann
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

  • MODY
  • LADA
  • diabetes late complications
  • molecular mechanisms
  • omics
  • polyneuropathy
  • microvascular disease
  • macrovascular disease
  • liver disease

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Published Papers (5 papers)

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Research

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17 pages, 4219 KiB  
Article
Identification of Differentially Expressed Genes and Pathways in Non-Diabetic CKD and Diabetic CKD by Integrated Human Transcriptomic Bioinformatics Analysis
by Clara Barrios, Marta Riera, Eva Rodríguez, Eva Márquez, Jimena del Risco, Melissa Pilco, Jorge Huesca, Ariadna González, Claudia Martyn, Jordi Pujol, Anna Buxeda and Marta Crespo
Int. J. Mol. Sci. 2025, 26(15), 7421; https://doi.org/10.3390/ijms26157421 - 1 Aug 2025
Viewed by 249
Abstract
Chronic kidney disease (CKD) is a heterogeneous condition with various etiologies, including type 2 diabetes mellitus (T2D), hypertension, and autoimmune disorders. Both diabetic CKD (CKD_T2D) and non-diabetic CKD (CKD_nonT2D) share overlapping clinical features, but understanding the molecular mechanisms underlying each subtype and distinguishing [...] Read more.
Chronic kidney disease (CKD) is a heterogeneous condition with various etiologies, including type 2 diabetes mellitus (T2D), hypertension, and autoimmune disorders. Both diabetic CKD (CKD_T2D) and non-diabetic CKD (CKD_nonT2D) share overlapping clinical features, but understanding the molecular mechanisms underlying each subtype and distinguishing diabetic from non-diabetic forms remain poorly defined. To identify differentially expressed genes (DEGs) and enriched biological pathways between CKD_T2D and CKD_nonT2D cohorts, including autoimmune (CKD_nonT2D_AI) and hypertensive (CKD_nonT2D_HT) subtypes, through integrative transcriptomic analysis. Publicly available gene expression datasets from human glomerular and tubulointerstitial kidney tissues were curated and analyzed from GEO and ArrayExpress. Differential expression analysis and Gene Set Enrichment Analysis (GSEA) were conducted to assess cohort-specific molecular signatures. A considerable overlap in DEGs was observed between CKD_T2D and CKD_nonT2D, with CKD_T2D exhibiting more extensive gene expression changes. Hypertensive-CKD shared greater transcriptomic similarity with CKD_T2D than autoimmune-CKD. Key DEGs involved in fibrosis, inflammation, and complement activation—including Tgfb1, Timp1, Cxcl6, and C1qa/B—were differentially regulated in diabetic samples, where GSEA revealed immune pathway enrichment in glomeruli and metabolic pathway enrichment in tubulointerstitium. The transcriptomic landscape of CKD_T2D reveals stronger immune and metabolic dysregulation compared to non-diabetic CKD. These findings suggest divergent pathological mechanisms and support the need for tailored therapeutic approaches. Full article
(This article belongs to the Special Issue Molecular Mechanism and Treatment of Diabetes Mellitus and Its Complications)
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13 pages, 1462 KiB  
Article
Targeting PAD4: A Promising Strategy to Combat β-Cell Loss in Type 1 Diabetes
by Hsu Lin Kang, András Szász, Zsuzsanna Valkusz, Tamás Várkonyi, Anikó Pósa and Krisztina Kupai
Int. J. Mol. Sci. 2025, 26(13), 6113; https://doi.org/10.3390/ijms26136113 - 25 Jun 2025
Viewed by 531
Abstract
Peptidylarginine deiminase 4 (PAD4) catalyzes protein citrullination, a post-translational modification implicated in type 1 diabetes mellitus (T1DM). This study examined PAD4 expression and activity in the pancreas of streptozotocin (STZ)-induced diabetic Wistar rats. Animals were divided into three groups: (A) STZ-induced diabetic rats [...] Read more.
Peptidylarginine deiminase 4 (PAD4) catalyzes protein citrullination, a post-translational modification implicated in type 1 diabetes mellitus (T1DM). This study examined PAD4 expression and activity in the pancreas of streptozotocin (STZ)-induced diabetic Wistar rats. Animals were divided into three groups: (A) STZ-induced diabetic rats (60 mg/kg, i.p.), (B) non-diabetic controls, and (C) diabetic rats treated with Cl-amidine (5 mg/kg), a pan-PAD inhibitor, from week six post-induction. Analyses included PAD4 mRNA and protein expression, citrullinated histone H3 (CitH3), calcium concentration, and neutrophil elastase activity. Diabetic rats exhibited increased PAD4 expression, CitH3 levels, and NETosis markers, alongside reduced pancreatic calcium, suggesting calcium consumption during PAD4 activation. Cl-amidine treatment attenuated NETosis. These results implicate PAD4 in T1DM pathogenesis via NETosis and support the utility of STZ-induced diabetic rats as a model for PAD4-targeted studies. Cl-amidine may represent a promising therapeutic approach to reduce pancreatic inflammation in T1DM. Full article
(This article belongs to the Special Issue Molecular Mechanism and Treatment of Diabetes Mellitus and Its Complications)
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25 pages, 5453 KiB  
Article
Effects of High Glucose on Simulated Ischemia/Reperfusion Injury in Isolated Cardiomyocytes
by Miriam J. K. Walter, Masakazu Shiota, Zhu Li, Matthew B. Barajas, Takuro Oyama and Matthias L. Riess
Int. J. Mol. Sci. 2025, 26(13), 6050; https://doi.org/10.3390/ijms26136050 - 24 Jun 2025
Viewed by 2407
Abstract
The rising prevalence of type 2 diabetes is linked to an increased risk of cardiovascular diseases, with the diabetic heart being particularly vulnerable to ischemia–reperfusion (IR) injury. Chronic hyperglycemia contributes to an increase in reactive oxygen species and impacts the homeostasis of biochemical [...] Read more.
The rising prevalence of type 2 diabetes is linked to an increased risk of cardiovascular diseases, with the diabetic heart being particularly vulnerable to ischemia–reperfusion (IR) injury. Chronic hyperglycemia contributes to an increase in reactive oxygen species and impacts the homeostasis of biochemical pathways, including the polyol pathway, increasing susceptibility to damage. Aldose reductase (AR), a key enzyme in this pathway, has been targeted for therapeutic intervention, with AR inhibitors showing potential in mitigating diabetic complications. This study investigated IR injury in cardiomyocytes following high glucose exposure and assessed the AR inhibitor Epalrestat as a protective agent. Cardiomyocyte function was evaluated by measuring lactate dehydrogenase (LDH) release, FM1-43 membrane incorporation, cell viability, intracellular calcium accumulation, and superoxide anion formation. High glucose exposure and simulated IR led to increased LDH release, FM1-43 incorporation, intracellular calcium, and superoxide levels, alongside reduced cell viability in a dose-dependent manner. However, Epalrestat treatment during high glucose exposure significantly reduced IR-induced injury. These findings suggest that high glucose exacerbates IR injury in cardiomyocytes, with the polyol pathway playing a critical role. Targeting this pathway with AR inhibitors like Epalrestat may offer a protective strategy against diabetic heart complications. Full article
(This article belongs to the Special Issue Molecular Mechanism and Treatment of Diabetes Mellitus and Its Complications)
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Review

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19 pages, 3309 KiB  
Review
Obesity-Related Glomerulosclerosis—How Adiposity Damages the Kidneys
by Justyna Zbrzeźniak-Suszczewicz, Agata Winiarska, Agnieszka Perkowska-Ptasińska and Tomasz Stompór
Int. J. Mol. Sci. 2025, 26(13), 6247; https://doi.org/10.3390/ijms26136247 - 28 Jun 2025
Viewed by 1073
Abstract
Obesity, hypertension, and chronic kidney disease (CKD) constitute the deadly trinity of modern threats for populations of both developed and developing countries. These diseases (together with type 2 diabetes) are closely linked in their pathophysiology and result in increasing cardiovascular (CV) morbidity and [...] Read more.
Obesity, hypertension, and chronic kidney disease (CKD) constitute the deadly trinity of modern threats for populations of both developed and developing countries. These diseases (together with type 2 diabetes) are closely linked in their pathophysiology and result in increasing cardiovascular (CV) morbidity and premature death from CV causes. In this review, we focused on the kidney as the target of obesity-related disorders. Obesity-related glomerulosclerosis (ORG) represents a pattern of renal injury caused solely or predominantly by obesity; usually, it is superimposed on chronic kidney disease (CKD) from other causes, such as diabetic kidney disease, hypertensive kidney disease, type 2 cardiorenal syndrome, primary or secondary glomerulopathies, and others. Adipose tissue contributes to kidney injury in several ways: it releases proinflammatory cytokines and growth factors, leading to podocyte and mesangial cell injury and glomerulosclerosis. In particular, perirenal adipose tissue (PRAT), besides exerting paracrine and endocrine effects on the kidney, modifies its function via compression on renal parenchyma and vessels. The intrinsic ability of the kidneys in obesity to increase the reabsorption of sodium warrants intraglomerular hypertension and hyperfiltration, followed by progressive renal injury. Lifestyle interventions and pharmacological agents, as well as metabolic (bariatric) surgery resulting in weight reduction, may also be beneficial for the kidneys. Using GLP1 receptor agonists (with a special focus on subcutaneous semaglutide and tirzepatide) seems to be the most promising treatment strategy for preventing kidney injury in obese individuals. Full article
(This article belongs to the Special Issue Molecular Mechanism and Treatment of Diabetes Mellitus and Its Complications)
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17 pages, 544 KiB  
Review
Diabetes Mellitus in Kidney Transplant Recipients and New Hypoglycemic Agent Options
by Giulia Bartoli, Andrea Dello Strologo, Maria Arena, Maria Josè Ceravolo, Anna Paola Mitterhofer, Francesco Pesce and Giuseppe Grandaliano
Int. J. Mol. Sci. 2025, 26(13), 5952; https://doi.org/10.3390/ijms26135952 - 20 Jun 2025
Viewed by 847
Abstract
Diabetes mellitus (DM) is frequent in kidney transplant recipients (KTRs), reducing graft and patient survival. In recent years, hypoglycemic agents have been approved for chronic kidney disease (CKD) patients, such as sodium glucose co-transporter type 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP1RAs), [...] Read more.
Diabetes mellitus (DM) is frequent in kidney transplant recipients (KTRs), reducing graft and patient survival. In recent years, hypoglycemic agents have been approved for chronic kidney disease (CKD) patients, such as sodium glucose co-transporter type 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP1RAs), and nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs), such as finerenone. Several studies demonstrated the ability of these drugs to reduce cardiovascular (CV) events and kidney disease progression in diabetic CKD patients. In this review, we will describe their use in KTRs with type 2 DM or post-transplant diabetes mellitus (PTDM), focusing on the potential positive effects. In particular, we will report literature data from observational studies, meta-analyses, and clinical trials. Based on their mechanism of actions, these drugs may balance the negative effects of immunosuppressive therapy on metabolic balance, reducing the risk of PTDM and CV events, that remain the first cause of death in KTRs. Generally, SGLT2is and GLP1RAs appear to be safe and efficacious in KTRs, and no interaction with immunosuppressive drugs or an increased risk of rejection has been reported. Regarding finerenone, no literature data are available and only one clinical trial is ongoing. In conclusion, although the 2022 KDIGO guidelines recommend caution in KTRs, the last meeting in Vienna on PTDM encourages their use in this population. Full article
(This article belongs to the Special Issue Molecular Mechanism and Treatment of Diabetes Mellitus and Its Complications)
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