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Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition)

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 18380

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Dr. Tomislav Bulum

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1. Department of Diabetes and Endocrinology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Zagreb, Croatia
2. Medical Faculty, University of Zagreb, Šalata 2, 10000 Zagreb, Croatia
Interests: diabetes type 1; diabetes type 2; metabolic syndrome; diabetic nephropathy; diabetic retinopathy
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Dear Colleagues,

Diabetes, one of the most challenging health problems of the 21st century, is projected to affect 700 million people by 2045. In the last 15 years, the number of people diagnosed with type 1 diabetes has increased by 45%, and the number diagnosed with type 2 diabetes by 95%. The most devastating effects of diabetes are its chronic complications, which confer a high risk of morbidity and mortality and represent an increased cost burden on health systems. Despite the increased awareness of and new therapeutic options for the treatment of diabetes, it is still the leading cause of blindness in working-age adults, kidney failure and dialysis, and nontraumatic lower-limb amputations. People with diabetes have a two- to four-times higher risk of developing cardiovascular disease, which remains the most common cause of death in people with this disease. Diabetes is a heterogenous and complex disease, and in addition to the traditional risk factors, such as hyperglycemia, hypertension, and dyslipidemia, multiple cellular pathways and potential molecular mechanisms are also implicated in diabetes-induced complications.

Considering this context, we welcome submissions to this Special Issue focusing on diabetes it terms of its comorbidities and therapeutics, as well as contributions providing insights into this disease. Improving our knowledge of diabetes will aid in the prevention of chronic complications and cardiovascular disease/death and in optimizing patients’ quality of life.

Dr. Tomislav Bulum
Guest Editor

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Keywords

diabetes
complications
diabetic retinopathy
diabetic neuropathy
diabetic nephropathy
biomarkers

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Published Papers (8 papers)

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Research

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17 pages, 3653 KB

Open AccessArticle

Intracellular Vesicle Transport Impairment as a Candidate Systems-Level Bottleneck in Chronic Diabetic Foot Ulcers: Network Medicine Identifies KIF13A as a Potential Therapeutic Vulnerability

by Haitao Ren and Yongan Xu

Biomedicines 2026, 14(5), 1140; https://doi.org/10.3390/biomedicines14051140 - 18 May 2026

Viewed by 318

Abstract

Background: Growth factor therapy often fails in diabetic foot ulcers (DFUs). The reason remains unclear. Standard differential expression analysis may miss functionally critical genes with modest expression changes. Methods: We performed a secondary computational analysis of a longitudinal DFU transcriptomic dataset (Dryad; 17 patients, 117 serial biopsy samples, 12-week follow-up). Co-expression networks were built separately for healed (n = 37) and non-healed (n = 80) samples. Virtual gene knockout (VGK) was used to rank genes by topological impact on network cohesion. Single-cell analysis (GSE165816) assessed the association between endogenous KIF13A expression and keratinocyte migration-related signatures. A conceptual Hill-equation simulation was used to illustrate the transport-signaling threshold relationship. Drug repurposing used DSigDB enrichment. An independent bulk DFU cohort (GSE134431) was used for external validation. Results: KIF13A showed no differential expression (log₂FC = 0.173, p = 0.263) yet ranked first by VGK topological impact. In keratinocytes, high KIF13A expression correlated with greater migration scores versus zero-detection cells (p = 0.0058). A clear threshold effect emerged: below the 30th expression percentile, EGF, PDGF, and FGF pathway activation scores remained near baseline. In a structural-equation model, transport activity negatively predicted inflammation (standardized β = −0.92, p < 0.001). HIF1A showed the strongest positive correlation with KIF13A in keratinocytes (Spearman ρ = 0.26, p < 0.001), and FOS showed a negative correlation in the single-cell analysis (ρ = −0.16, p < 0.001) and in the bulk longitudinal cohort (ρ = −0.32, p < 0.001, n = 117). Recurrent AKR1B1-related drug signatures nominated the aldose-reductase pathway, and epalrestat was therefore prioritized as a hypothesis-generating candidate compound rather than a direct top-ranked enrichment hit. External validation confirmed consistent upregulation of KIF13A (Fold-Change = 1.58, adj. p = 0.0075), EPN1, and CLIP1 in DFU tissue. Despite population-level upregulation, a subset of cells fell below the functional signaling threshold. Conclusions: These computational findings suggest that KIF13A-associated vesicle transport impairment may represent a candidate systems-level bottleneck for growth-factor responsiveness in DFUs, a network-level pattern not captured by standard differential-expression analysis. Epalrestat, an AKR1B1 inhibitor prioritized through recurrent AKR1B1-related drug signatures, is presented as a candidate compound for further evaluation. As the present analysis is observational and computational, the findings should be interpreted as hypothesis-generating; experimental perturbation studies and prospective clinical validation are required. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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13 pages, 1642 KB

Open AccessArticle

Ultrasound-Assisted Wound Debridement for Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Shasha Mei, Hua Chen and Jiezhi Dai

Biomedicines 2026, 14(4), 846; https://doi.org/10.3390/biomedicines14040846 - 8 Apr 2026

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Abstract

Background: Diabetic foot ulcers (DFUs) represent a severe and costly complication of diabetes mellitus. This meta-analysis aims to compare the efficacy of ultrasound-assisted wound debridement (UAWD) and conventional debridement in promoting wound healing in patients with DFUs. Methods: A systematic literature search was conducted using PubMed, EMBASE, BIOSIS, Web of Science, and the Cochrane Library from inception to 31 October 2025. Randomized controlled trials (RCTs) that compared UAWD with a placebo or standard wound care in patients with DFUs were included. Primary outcomes were the healing rate, time to complete healing, and reduction in wound area. Results were expressed as odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs). This study was registered on the PROSPERO platform (CRD420251229633). Results: Ten RCTs that involved 386 patients were included. The meta-analysis showed that the treatment group had a significantly higher complete wound healing rate compared with the control group (OR: 2.92; 95% CI: 1.82 to 4.70; p = 0.75; I² = 0%). The rate of wound area reduction was also significantly greater in the treatment group (MD: 21.29%; 95% CI: 3.03 to 39.56; p = 0.003; I² = 75%). Furthermore, the time to complete healing was significantly shorter in the treatment group (MD: −4.84 weeks; 95% CI: −8.65 to −1.03; I² = 61%, p = 0.05). Conclusions: UAWD appears to be more effective than conventional debridement alone in improving healing rates and accelerating wound closure in diabetic foot ulcers. However, safety data were inadequately reported across most included studies, with adverse events poorly characterized. Future large-scale RCTs should prioritize rigorous adverse event reporting to establish both the efficacy and safety profile of this intervention. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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14 pages, 1316 KB

Open AccessArticle

Branched-Chain Amino Acid Intake and Risk of Incident Type 2 Diabetes: Results from the SUN Cohort

by Víctor de la O, Telmo Bretos-Azcona, Francisco Javier Basterra-Gortari, Carmen de la Fuente-Arrillaga, Miguel Ruiz-Canela, Miguel Ángel Martínez-González and Maira Bes-Rastrollo

Biomedicines 2025, 13(10), 2561; https://doi.org/10.3390/biomedicines13102561 - 21 Oct 2025

Cited by 1 | Viewed by 1250

Abstract

Background/Objectives: While many studies have explored the association between circulating branched-chain amino acids (BCAAs) and type 2 diabetes mellitus (T2DM), evidence on the prospective relationship between dietary BCAA intake and T2DM risk remains limited. We aimed to explore this relationship—both total and by dietary source—in a Mediterranean cohort. Methods: We used data from the SUN Project, a prospective and dynamic cohort of Spanish university graduates initiated in 1999. Dietary intake was assessed with a validated 136-item food frequency questionnaire at baseline and at 10 years. BCAA intake (valine, leucine, isoleucine) was estimated using the USDA amino acid database and adjusted for energy intake by the residual method. Participants were followed biennially through questionnaires to identify incident T2DM cases, confirmed by a supplementary questionnaire and medical report, following the ADA diagnostic criteria. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for potential confounders across four multivariable models. BCAA intake was modeled both categorically (tertiles) and continuously (per 0.5% energy or 5 g/day increase). Analyses were stratified by age and recruitment period. Results: After exclusions, 20,154 participants were included (mean follow-up: 14.67 ± 5.8 years), with 220 incident T2DM cases identified. For each 0.5% energy increment intake from BCAA, there was no association with T2DM (adjusted HR: 1.01; 95% CI: 0.69–1.20). Among men, the adjusted HR was 0.91, 95% CI: 0.69–1.20. Among women, it was 1.40, 95% CI: 0.94–2.09. In the overall cohort, higher BCAA intake showed a non-significant inverse association with the T2DM risk when comparing extreme tertiles (HR = 0.81; 95% CI: 0.48–1.37), which strengthened when repeated dietary measures were considered (HR = 0.70; 95% CI: 0.46–1.06, p-trend = 0.06). Analyses by BCAA sources (animal vs. plant) and stratified by sex, weight status, and age did not reveal consistent patterns, though exploratory findings suggested potential effect modification by sex and adiposity. Sensitivity analyses confirmed the lack of robust associations, with some subgroup-specific signals being limited by low event numbers and wide CIs. Conclusions: Given the power limitations and the modest, non-significant associations observed, these findings should be considered preliminary evidence that may help guide future research on the role of dietary BCAAs in glucose metabolism and diabetes risk. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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19 pages, 1382 KB

Open AccessArticle

Public Health Screening for Cardiometabolic Risk: Lessons from Advanced Glycation End-Products and ABC Target Achievement in Dalmatian Adults with Type 2 Diabetes

by Josipa Radić, Marijana Vučković, Hana Đogaš, Anders Ødeverp, Marina Grubić and Mislav Radić

Biomedicines 2025, 13(10), 2418; https://doi.org/10.3390/biomedicines13102418 - 2 Oct 2025

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Abstract

Background/Objectives: Cardiometabolic risk remains a major challenge in patients with type 2 diabetes mellitus (DMT2). This study aimed to evaluate cardiovascular (CV) risk stratification using advanced glycation end-products (AGEs) measured via skin autofluorescence (SAF) and to assess the achievement of evidence-based ABC targets (HbA1c, blood pressure, low-density lipoprotein (LDL) cholesterol) in adults with DMT2 in Dalmatia. Methods: In this single-center cross-sectional study, 251 adults with DMT2 were stratified by CV risk based on SAF measured AGE levels. Clinical, biochemical, and anthropometric data were collected, including ABC goal attainment and medication use. Statistical analyses compared groups and explored predictors of ABC target achievement using regression models adjusted for clinical factors. Results: Only 17.5% of participants achieved all three ABC goals, indicating suboptimal cardiometabolic control. Those with elevated CV risk had higher hip circumference and lower diastolic blood pressure. Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors was positively associated with ABC goal achievement in patients with prior CV or cerebrovascular events, while higher body mass index was negatively associated. SAF measured AGE levels correlated with cardiometabolic risk but showed no significant differences across LDL cholesterol or other traditional markers. Conclusions: SAF AGE measurement shows potential for CV risk stratification in DMT2 beyond traditional factors. The low rate of ABC goal attainment highlights the need for intensified individualized management incorporating novel biomarkers and therapeutics like SGLT2 inhibitors. Further prospective studies are needed to validate these findings and improve prevention of cardiovascular complications in DMT2. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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22 pages, 1022 KB

Open AccessArticle

Correlations Between Coffee Intake, Glycemic Control, Cardiovascular Risk, and Sleep in Type 2 Diabetes and Hypertension: A 12-Month Observational Study

by Tatiana Palotta Minari, José Fernando Vilela-Martin, Juan Carlos Yugar-Toledo and Luciana Pellegrini Pisani

Biomedicines 2025, 13(8), 1875; https://doi.org/10.3390/biomedicines13081875 - 1 Aug 2025

Cited by 1 | Viewed by 8079

Abstract

Background: The consumption of coffee has been widely debated regarding its effects on health. This study aims to analyze the correlations between daily coffee intake and sleep, blood pressure, anthropometric measurements, and biochemical markers in individuals with type 2 diabetes (T2D) and hypertension over a 12-month period. Methods: An observational study was conducted with 40 participants with T2D and hypertension, comprising 20 females and 20 males. Participants were monitored for their daily coffee consumption over a 12-month period, being assessed every 3 months. Linear regression was utilized to assess interactions and relationships between variables, providing insights into potential predictive associations. Additionally, correlation analysis was performed using Pearson’s and Spearman’s tests to evaluate the strength and direction of linear and non-linear relationships. Statistical significance was set at p < 0.05. Results: Significant changes were observed in fasting blood glucose (FBG), glycated hemoglobin (HbA1c), body weight, body mass index, sleep duration, nocturnal awakenings, and waist-to-hip ratio (p < 0.05) over the 12-month study in both sexes. No significant differences were noted in the remaining parameters (p > 0.05). The coffee consumed by the participants was of the “traditional type” and contained sugar (2 g per cup) for 100% of the participants. An intake of 4.17 ± 0.360 cups per day was found at baseline and 5.41 ± 0.316 cups at 12 months (p > 0.05). Regarding correlation analysis, a higher coffee intake was significantly associated with shorter sleep duration in women (r = −0.731; p = 0.037). Conversely, greater coffee consumption correlated with lower LDL cholesterol (LDL-C) levels in women (r = −0.820; p = 0.044). Additionally, a longer sleep duration was linked to lower FBG (r = −0.841; p = 0.031), HbA1c (r = −0.831; p = 0.037), and LDL-C levels in women (r = −0.713; p = 0.050). No significant correlations were observed for the other parameters in both sexes (p > 0.05). Conclusions: In women, coffee consumption may negatively affect sleep duration while potentially offering beneficial effects on LDL-C levels, even when sweetened with sugar. Additionally, a longer sleep duration in women appears to be associated with improvements in FBG, HbA1c, and LDL-C. These correlations emphasize the importance of a balanced approach to coffee consumption, weighing both its potential health benefits and drawbacks in postmenopausal women. However, since this study does not establish causality, further randomized clinical trials are warranted to investigate the underlying mechanisms and long-term implications—particularly in the context of T2D and hypertension. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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Review

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21 pages, 1403 KB

Open AccessReview

Integrating GLP-1 Receptor Agonists into Modern Stroke Prevention: Evidence, Mechanisms, and Clinical Consideration—A Narrative Review

by Shayan Khan, William Herbst, Farbod Zahedi Tajrishi, Sonali Notani, Alexander Knight, Zina Jamil and Keith C. Ferdinand

Biomedicines 2026, 14(4), 743; https://doi.org/10.3390/biomedicines14040743 - 24 Mar 2026

Cited by 1 | Viewed by 1378

Abstract

Stroke remains a major cause of morbidity and mortality worldwide. Although reperfusion therapies and secondary prevention have advanced, the global stroke burden continues to rise, driven by increasing rates of hypertension and diabetes mellitus. Type 2 diabetes (T2DM) increases the risk of acute ischemic stroke (AIS) through mechanisms involving chronic hyperglycemia, endothelial dysfunction, inflammation, and accelerated atherogenesis. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents for cardiovascular and cerebrovascular risk reduction in patients with T2DM. Beyond their glucose-lowering properties, GLP-1RAs improve blood pressure regulation and lipid metabolism, as mentioned in the 2025 AHA Journal guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults. Emerging preclinical and clinical evidence indicates that GLP-1RAs also provide direct neurovascular protection by stabilizing the blood–brain barrier, modulating neuroinflammation, and promoting neuronal survival. These mechanisms may reduce ischemic injury, improve recovery after stroke, and protect against cognitive decline. Major cardiovascular outcome trials have demonstrated significant reductions in major adverse cardiovascular events and, to a lesser degree, non-fatal stroke among patients receiving GLP-1RAs. This narrative review evaluates current evidence on the neurovascular, cardiometabolic, and anti-inflammatory actions of GLP-1RAs and their potential role in mitigating stroke risk and promoting cerebrovascular health. Additionally, it highlights gaps in the literature, explores clinical and guideline implications, and outlines future directions for integrating GLP-1RA therapy into comprehensive stroke prevention and recovery strategies. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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35 pages, 2046 KB

Open AccessSystematic Review

Advances in Image-Based Diagnosis of Diabetic Foot Ulcers Using Deep Learning and Machine Learning: A Systematic Review

by Haifa F. Alhasson and Shuaa S. Alharbi

Biomedicines 2025, 13(12), 2928; https://doi.org/10.3390/biomedicines13122928 - 28 Nov 2025

Cited by 2 | Viewed by 2778

Abstract

Background/Objectives: This review systematically assesses machine learning (ML) and deep learning (DL) applications using images to diagnose diabetic foot ulcers (DFUs), focusing on detection, segmentation, and classification. The study explores trends, challenges, and quality measurements of the reviewed research. Methods: A comprehensive search was conducted in October 2025 across 14 databases, covering studies published between 2010 and 2025. Studies employing ML/DL for DFU diagnosis with accurate measurements were included, while those without image-based methods, AI techniques, or relevant outcomes were excluded. Out of 4653 articles initially identified, 1016 underwent detailed review, and 102 met the inclusion criteria. Results: The analysis revealed that ML/DL models are effective tools for DFU diagnosis, achieving accuracy between 0.88 and 0.97, specificity between 0.85 and 0.95, and sensitivity between 0.89 and 0.95. Common methods included Support Vector Machines (SVMs) for ML and U-Net or fully convolutional neural networks (FCNNs) for DL. Recent studies also explored thermal infrared imaging as a promising diagnostic technique. However, only 45% of segmentation datasets and 67.3% of classification datasets were publicly accessible, limiting reproducibility and further development. Conclusions: This review provides valuable insights into trends and key findings in ML/DL applications for DFU diagnosis. It highlights the need for improved data availability and sharing to enhance reproducibility, accuracy, and reliability, ultimately improving patient care. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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5 pages, 159 KB

Open AccessViewpoint

Intraductal Papillary Mucinous Neoplasms and GLP-1 Receptor Agonists: Navigating Therapeutic Uncertainty in Diabetes Management

by Francesco Tassone and Giovanna Saraceno

Biomedicines 2025, 13(10), 2326; https://doi.org/10.3390/biomedicines13102326 - 23 Sep 2025

Viewed by 1749

Abstract

The management of type 2 diabetes in patients with intraductal papillary mucinous neoplasms (IPMNs) presents a growing clinical dilemma. As glucagon-like peptide-1 receptor agonists (GLP-1RAs) become first-line therapies for diabetes and obesity, their safety in patients with premalignant pancreatic lesions remains uncertain. This viewpoint examines current evidence through three critical lenses: molecular mechanisms linking incretin signaling to IPMN progression, clinical outcomes from large-scale pharmacovigilance studies, and practical management considerations. We propose a risk-stratified approach that balances the proven metabolic benefits of GLP-1RAs against theoretical oncogenic risks, emphasizing the need for shared decision-making and enhanced surveillance protocols. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (3rd Edition))

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