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Diabetes: Comorbidities, Therapeutics and Insights (2nd 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: closed (30 April 2025) | Viewed by 4661

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Dr. Tomislav Bulum

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1. Vuk Vrhovac Univerity Clinic, Merkur University Hospital, Zajčeva 19, 10000 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 is one of the most challenging health problems of the 21st century, being projected to affect 700 million people by 2045. In the last 15 years, the number of people diagnosed with type 1 diabetes increased by 45%, and those diagnosed with type 2 diabetes increased by 95%. The most devastating effects of diabetes are its chronic complications, which confer a high risk of morbidity and mortality and an increased health system cost burden. Although there is increased awareness and new therapeutic options in the treatment of diabetes, it is still the leading cause of blindness in working-age adults, the leading cause of kidney failure and dialysis, and the leading cause of 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 diabetes. Diabetes is a very 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 comorbidities, therapeutics, and insights into this disease. Detailed knowledge of this harmful disease is needed to prevent chronic complications and cardiovascular disease/death and optimize 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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Diabetes: Comorbidities, Therapeutics and Insights in Biomedicines (17 articles)

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13 pages, 1776 KiB

Open AccessArticle

Altered IgG N-Glycosylation at Onset of Type 1 Diabetes in Children Is Predominantly Driven by Changes in the Fab N-Glycans

by Branimir Plavša, Najda Rudman, Flemming Pociot and Olga Gornik

Biomedicines 2025, 13(5), 1206; https://doi.org/10.3390/biomedicines13051206 - 15 May 2025

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Abstract

Background: N-glycosylation is a post-translational modification involving the attachment of oligosaccharides to proteins and is known to influence immunoglobulin G (IgG) effector functions and even antigen binding. IgG contains an evolutionarily conserved N-glycosylation site in its fragment crystallizable (Fc) region, while during V-D-J recombination and somatic hypermutation processes it can also obtain N-glycosylation sites in its antigen binding fragment (Fab). Our previous study demonstrated altered IgG N-glycosylation in children at type 1 diabetes (T1D) onset, with the most prominent changes involving sialylated glycans, hypothesized to mainly come from the Fab region, however, the analytical method used could not distinguish between Fc and Fab. Methods: IgG was isolated from plasma from 118 children with T1D and 98 healthy controls from the Danish Registry of Childhood and Adolescent Diabetes. Isolated IgG was cleaved into Fc and Fab fragments using IdeS enzyme. N-glycans were enzymatically released from each fragment, fluorescently labelled with procainamide, and analyzed separately using the UPLC-MS method. Structural annotation of resulting chromatograms was performed using MS/MS. Results: T1D related N-glycosylation changes were more pronounced in the Fab glycans compared to Fc glycans, with five Fab glycans (Man5, Man7, FA2BG1S1, A2G2S2, FA2BG2S1) being significantly altered compared to only one in the Fc region (FA2[3]BG1). Comparing Fc and Fab glycosylation overall reveals stark differences in the types of glycans on each region, with a more diverse and complex repertoire being present in the Fab region. Conclusions: These findings suggest that N-glycosylation changes in early onset T1D predominantly originate from the Fab region, underscoring their potential role in modulating (auto)immunity and highlighting distinct glycosylation patterns between Fc and Fab. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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25 pages, 3444 KiB

Open AccessArticle

Molecular Ancestry Across Allelic Variants of SLC22A1, SLC22A2, SLC22A3, ABCB1, CYP2C8, CYP2C9, and CYP2C19 in Mexican-Mestizo DMT2 Patients

by Adiel Ortega-Ayala, Carla González de la Cruz, Pedro Dorado, Fernanda Rodrigues-Soares, Fernando Castillo-Nájera, Adrián LLerena and Juan Molina-Guarneros

Biomedicines 2025, 13(5), 1156; https://doi.org/10.3390/biomedicines13051156 - 9 May 2025

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Background/Aims: across protein-coding genes, single nucleotide allelic variants (SNVs) affect antidiabetic drug pharmacokinetics, thus contributing to interindividual variability in drug response. SNV frequencies vary across different populations. Studying ancestry proportions among SNV genotypes is particularly important for personalising diabetes mellitus type 2 (DMT2) treatment. Methods: a sample of 249 Mexican DMT2 patients was gathered. SNVs were determined through real-time PCR (RT-PCR). Molecular ancestries were determined as 3 clusters (Native-American, European, and African) based upon 90 ancestry markers (AIMS). Statistical inference tests were performed to analyse ancestry across 23 SNV genotypes. Allele and ancestry distributions were analysed through Spearman’s correlation. Results: ancestry medians were 65.48% Native-American (NATAM), 28.34% European (EUR), and 4.8% African (AFR). CYP2C8*3 and CYP2C8*4 were negatively correlated to NATAM, whereas positively to EUR. The activity score of CYP2C9 was correlated to NATAM (Rho = 0.131, p = 0.042). CYP2C19*17 and the activity score of CYP2C19 were negatively correlated to NATAM. The correlation throughout SLC22A1 variants, such as GAT in rs72552763, was positive by EUR, while A in rs594709 was negative thereby and positive by NATAM. SLC22A3 variant C in rs2076828 was positively correlated to NATAM. NATAM patients present higher HbA1c levels with respect to Mestizo patients (p = 0.037). Uncontrolled patients (HbA1c ≥ 7%) have a larger NATAM ancestry (p = 0.018) and lower EUR (p = 0.022) as compared to controlled patients (HbA1c < 7%). Conclusions: there is a correlation between ancestry and some pharmacokinetically relevant alleles among Mexican DMT2 patients. Ethnicity is relevant for personalised medicine across different populations. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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10 pages, 774 KiB

Open AccessArticle

Nutrition Indicators in Type 2 Diabetes Mellitus—Retrospective Study

by Jakub Piersa, Wiktoria Bajek, Aleksandra Pilśniak, Agnieszka Jarosińska, Marta Pietrukaniec and Michał Holecki

Biomedicines 2025, 13(5), 1137; https://doi.org/10.3390/biomedicines13051137 - 8 May 2025

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Background/Objectives: This study aims to evaluate the prevalence and degree of malnutrition among patients with type 2 diabetes mellitus using the CONUT and PNI scores. Hypothesis: The CONUT and PNI scores provide a reliable assessment of the nutritional status of patients with type 2 diabetes. Methods: The retrospective study was run at the Department of Internal, Autoimmune and Metabolic Diseases in the Central Clinical Hospital of the Medical University of Silesia in Katowice from January to December of 2022. From 266 patients diagnosed with diabetes, only 64 met the criteria and were included in this study. Results: We found varying degrees of malnutrition among patients. Only 20.3% of them were well nourished. Mild to moderate malnutrition was observed in, altogether, 67.2% of patients. Conclusions: The strong correlation between the CONUT and PNI (r = −0.88) indices confirms their diagnostic value. The introduction of the CONUT or PNI tools into routine practice should be considered in patients with T2DM, especially those over 65 years of age, but taking into account the significant limitations of these indices and the influence of various factors on the laboratory data considered. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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14 pages, 2422 KiB

Open AccessArticle

Prediction of Metabolic Parameters of Diabetic Patients Depending on Body Weight Variation Using Machine Learning Techniques

by Oana Vîrgolici, Daniela Lixandru, Andrada Mihai, Diana Simona Ștefan, Cristian Guja, Horia Vîrgolici and Bogdana Virgolici

Biomedicines 2025, 13(5), 1116; https://doi.org/10.3390/biomedicines13051116 - 4 May 2025

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Background/Objectives: Obesity is a major risk factor for diabetes mellitus, a metabolic disease characterized by elevated fasting blood glucose and glycosylated hemoglobin levels. Predicting the percentage and absolute variations in key medical parameters based on weight changes can help patients stay motivated to lose weight and assist doctors in making informed lifestyle and treatment recommendations. This study aims to assess the extent to which weight variation influences the absolute and percentage changes in various clinical parameters. Methods: The dataset includes medical records from patients in Bucharest hospitals, collected between 2012 and 2016. Several machine learning models, namely linear regression, polynomial regression, Gradient Boosting, and Extreme Gradient Boosting, were employed to predict changes in medical parameters as a function of body weight variation. Model performance was evaluated using Mean Squared Error, Mean Absolute Error, and R² score. Results: Almost all models demonstrated promising predictive performance. Quantitative predictions were made for each parameter, highlighting the relationship between weight loss and improvements in clinical indicators. Conclusions: Weight loss led to significant improvements in dysglycemia, dyslipidemia, inflammation, uric acid levels, liver enzymes, thyroid hormones, and blood pressure, with reductions ranging from 5% to 30%, depending on the parameter. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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10 pages, 458 KiB

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Risk Factors for the Development of Early Onset Diabetes in the Population of Sindh Province, Pakistan

by Eraj Abbas, Asher Fawwad, Iftikhar Ahmed Siddiqui, Muhammad Sohail Afzal, Muhammad Ansar, Muhammad Arif Nadeem Saqib and Syed M. Shahid

Biomedicines 2025, 13(5), 1107; https://doi.org/10.3390/biomedicines13051107 - 2 May 2025

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Abstract

Background/Objective: Early-onset diabetes (EOD), diagnosed at ≤35 years, is a growing public health crisis in low- and middle-income countries, including Pakistan. Identifying modifiable and non-modifiable risk factors is critical for developing effective prevention strategies. This study aimed to investigate the risk factors associated with EOD in Sindh, Pakistan, focusing on genetic, lifestyle, and metabolic determinants. Methods: A multicenter cross-sectional study was conducted across diabetic clinics in Sindh, with primary data collection at Baqai Institute of Diabetology and Endocrinology (Karachi, Pakistan) and secondary sites in Hyderabad, Larkana, and Sukkur. Following institutional ethical approval and informed consent, we enrolled 754 individuals (type 1 and type 2 diabetes, age at diagnosis: 15–35 years). Data on anthropometric, clinical, biochemical, and lifestyle parameters were collected via structured questionnaires. Statistical analyses included Pearson’s Chi Square tests and multivariate logistic regression in determining associations. Results: Logistic regression revealed key predictors of early-onset diabetes (EOD). A two-generation diabetes family history showed a strong association (aOR:1.86, 1.12–3.43). Significant lifestyle risks included physical inactivity (OR:1.40, 1.03–1.90), frequent sugary beverage intake (OR:1.93, 1.89–1.98), and abnormal sleep duration (<6 h: OR:1.58, 1.04–2.40; >8 h: OR:1.86, 1.21–2.85). Hypertension was a major metabolic predictor (elevated BP: OR:1.79, 1.28–1.54; Stage I: OR:1.81, 1.34–1.77). Cardiovascular disease and uncontrolled fasting glucose lost significance after adjustment, indicating confounding effects. Conclusions: This study highlights familial predisposition, sedentary behavior, poor diet, sleep disturbances, and hypertension as key contributors to EOD in young Pakistani adults. Early screening and targeted lifestyle interventions are urgently needed to mitigate this escalating epidemic. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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12 pages, 828 KiB

Open AccessArticle

Artificial Intelligence Algorithm to Screen for Diabetic Neuropathy: A Pilot Study

by Giovanni Sartore, Eugenio Ragazzi, Francesco Pegoraro, Mario German Pagno, Annunziata Lapolla and Francesco Piarulli

Biomedicines 2025, 13(5), 1075; https://doi.org/10.3390/biomedicines13051075 - 29 Apr 2025

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Abstract

Background/Objectives: Patients with type 2 diabetes (T2D) are at risk of developing multiple complications, and diabetic polyneuropathy (DPN) is by far the most common. The purpose of the present study was to assess the ability of a new algorithm based on artificial intelligence (AI) to identify patients with T2D who are at risk of DPN in order to move on to further instrumental evaluation with the biothesiometer method. Methods: This is a single-centre, cross-sectional study with 201 consecutive T2D patients recruited at the Diabetes Operating Unit of the ULSS 6 of Padua (Northeast Italy). The individual risk of developing DPN was calculated using the AI-based MetaClinic Prediction Algorithm and compared with the DPN diagnosis provided by the digital biothesiometer method, which measures the vibratory perception threshold (VPT) on both feet. Results: Of the enrolled patients, 107 (53.23%) were classified by AI software as having a low probability of developing DPN, 39 (19.40%) as having a moderate probability, 29 (14.43%) as having a high probability, and 26 (12.94%) as having a very high probability. In 63 of the total patients, biothesiometer measurement showed a VPT ≥ 25 V, indicative of DPN, while 138 patients had a non-pathological VPT value (< 25 V) (prevalence of abnormal VPT 31.34%; prevalence of normal VPT 68.66%). The overall agreement between biothesiometer results and AI risk attribution was 65%. Cohen’s κ was 0.162, and Gwet’s AC1 coefficient 0.405. Conclusions: The use of an optimized AI algorithm can help estimate the risk of developing DPN, thereby guiding more targeted and in-depth screening, including instrumental assessment using the biothesiometer method. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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18 pages, 2759 KiB

Open AccessArticle

The Risk of Vestibular Disorders with Semaglutide and Tirzepatide: Findings from a Large Real-World Cohort

by Eman A. Toraih, Awwad Alenezy, Mohammad H. Hussein, Shahmeer Hashmat, Saitej Mummadi, Nawaf Farhan Alrawili, Ahmed Abdelmaksoud and Manal S. Fawzy

Biomedicines 2025, 13(5), 1049; https://doi.org/10.3390/biomedicines13051049 - 26 Apr 2025

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Abstract

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of type 2 diabetes and obesity. While their metabolic benefits are well-established, their potential effects on vestibular function remain unexplored. This study investigated the association between GLP-1RA use and the risk of vestibular disorders. Methods: Using the TriNetX research network (accessed 3 November 2024), we conducted a retrospective cohort study of adults prescribed semaglutide (n = 419,497) or tirzepatide (n = 77,259) between January 2018 and October 2024. Cases were matched 1:1 with controls using propensity scores based on demographics and comorbidities. The primary outcome was new-onset vestibular disorders, analyzed at 6 months, 1 year, and 3 years after treatment initiation. Results: Both medications were associated with an increased risk of vestibular disorders. Semaglutide users showed a higher cumulative incidence (0.12% at 6 months to 0.41% at 3 years) compared to controls (0.03% to 0.16%, p < 0.001), with hazard ratios ranging from 4.02 (95% CI: 3.33–4.86) at 6 months to 4.95 (95% CI: 4.51–5.43) at 3 years. Tirzepatide users demonstrated similar patterns but lower absolute rates (0.10% at 6 months to 0.19% at 3 years vs. controls 0.04% to 0.15%), with hazard ratios from 3.19 (95% CI: 2.11–4.81) to 4.55 (95% CI: 3.43–6.03). The direct comparison showed a higher risk with semaglutide versus tirzepatide (RR 1.53–2.04, p < 0.001). Conclusions: GLP-1RA therapy is associated with an increased risk of vestibular disorders, with a higher risk observed with semaglutide compared to tirzepatide. These findings suggest the need for vestibular symptom monitoring in patients receiving these medications and warrant further investigation into underlying mechanisms. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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28 pages, 3440 KiB

Open AccessArticle

Multilevel Assessment of Glycemic, Hormonal, and Oxidative Parameters in an Experimental Diabetic Female Rat Model

by Iulian Tătaru, Ioannis Gardikiotis, Oana-Maria Dragostin, Luminita Confederat, Cerasela Gîrd, Alexandra-Simona Zamfir, Ionela Daniela Morariu, Carmen Lidia Chiţescu, Ancuța Dinu (Iacob), Liliana Costea Popescu and Carmen Lăcrămioara Zamfir

Biomedicines 2025, 13(4), 922; https://doi.org/10.3390/biomedicines13040922 - 9 Apr 2025

Viewed by 290

Abstract

Background: Diabetes mellitus induces profound metabolic and endocrine alterations, impacting reproductive function through oxidative stress and hormonal imbalances. This study investigated the effects of alloxan-induced diabetes on hormonal status and oxidative stress in female Wistar rats. Methods: A synthetic sulfonamide derivative (compound S) was obtained via chemical synthesis and characterized by elemental and spectral analysis. Salvia officinalis extract was phytochemically profiled using UHPLC-HRMS and assessed for antioxidant potential using DPPH, ABTS, and FRAP assays. The synthetic compound and the plant extract, along with metformin were evaluated in vivo for their potential antihyperglycemic, hormone-regulating, and antioxidant properties., Serum levels of progesterone, estradiol, and follicle-stimulating hormone (FSH) were evaluated alongside oxidative stress biomarkers transforming growth factor-beta 1 (TGF-β1) and glutathione peroxidase 3 (GPX3). Results: Diabetic rats (untreated) exhibited a significant decrease in estradiol (22.00 ± 4.1 pg/mL vs. 54.74 ± 17.5 pg/mL in controls, p < 0.001) and an increase in progesterone levels (17.38 ± 9.6 ng/mL vs. 3.59 ± 0.90 ng/mL in controls, p < 0.05), suggestive for ovarian dysfunction. TGF-β1 levels were elevated in diabetic rats (27.73 ± 19.4 ng/mL vs. 21.55 ± 13.15 ng/mL in controls, p < 0.05), while increased serum GPX3 (61.50 ± 11.3 ng/mL vs. 38.20 ± 12.84 ng/mL in controls, p < 0.05) indicates enhanced oxidative stress. Statistical analysis revealed a correlation between serum GPX3 levels, FSH (p = −0.039), and estradiol (p = −0.025) in the diabetic group (L2). Conclusions: These findings contribute new evidence regarding the effects of diabetes on reproductive hormones and oxidative stress in female models. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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12 pages, 249 KiB

Open AccessArticle

Association Between Hypertension, Dipping Status, and ACE and AGTR1 Gene Polymorphisms in Adolescents with Type 1 Diabetes

by Smiljka Kovacevic, Maja Jesic, Vera Zdravkovic, Stefan Djordjevic, Jelena Miolski, Vladimir Gasic, Marina Jelovac, Milena Ugrin, Sonja Pavlovic and Branko Subosic

Biomedicines 2025, 13(3), 615; https://doi.org/10.3390/biomedicines13030615 - 3 Mar 2025

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Abstract

Objectives: This study aims to show the distribution of angiotensin-converting enzyme (ACE) rs1799752 (I>D) gene insertion/deletion (I/D) polymorphism and angiotensin II receptor type 1 (AGTR1) rs5186 (A>C) gene polymorphism in adolescents with hypertension (HT) and type 1 diabetes (T1D), as well as its association with hypertension and the diurnal variation of mean blood pressure (dipping phenomenon). Methods: A cross-sectional study was conducted involving 118 adolescents diagnosed with T1D who underwent clinical and laboratory investigations, genetic analyses, and 24 h ambulatory blood pressure monitoring. The genotype frequencies were compared between adolescents with HT and those with normal blood pressure. Additionally, the genotype frequencies were compared between dippers and non-dippers. Results: Patients with HT were more likely to be female and exhibited significantly poorer glycemic control and higher triglycerides, along with increased body mass index and daily insulin dosage. The prevalence of ACE rs1799752 genotypes in the hypertensive group was 20% II, 66.7% ID, and 13.3% DD, which did not significantly differ from the normal blood pressure group with 29.1% II, 53.4% ID, and 17.5% DD (p = 0.625). The prevalence of AGTR1 rs5186 genotypes in the hypertensive group was 53.3% AC, 40% AA, and 6.7% CC, which also did not significantly differ from the normal blood pressure group with 39.8% AC, 52.4% AA, and 7.8% CC (p = 0.608). A total of 46% of the patients exhibited non-dipping phenomena. The prevalence of non-dippers among the ACE genotypes was 13% DD, 33.3% II, and 53.7% ID (p = 0.369), while for the AGTR1 genotypes, it was 50% AA, 42.6% AC, and 7.4% CC (p = 0.976). Conclusions: Our results indicate that in our adolescents with T1D, clinical and metabolic factors such as higher body mass index, triglycerides, suboptimal glycemic control, and female gender are more indicative of the development of hypertension than ACE and AGTR1 gene polymorphisms. A potential reason for this finding could be the young age of the patients or the relatively small size of the study group. Future research involving larger sample sizes is needed to further investigate the genetic predisposition for the development of hypertension. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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16 pages, 2440 KiB

Open AccessSystematic Review

Evaluating the Causal Association Between Type 2 Diabetes and Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study

by Si Han, Tom Lelieveldt, Miriam Sturkenboom, Geert Jan Biessels and Fariba Ahmadizar

Biomedicines 2025, 13(5), 1095; https://doi.org/10.3390/biomedicines13051095 - 30 Apr 2025

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Abstract

Background/Objectives: Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are significant global health issues. Epidemiological studies suggest T2DM increases AD risk, though confounding factors and reverse causality complicate this association. This study aims to clarify the causal relationship between T2DM and AD through a systematic review and meta-analysis of Mendelian randomization (MR) studies and a new two-sample MR analysis. Methods: A literature search across major databases was conducted through May 2024 to identify MR studies linking T2DM and AD. Fixed/random-effect models provided pooled odds ratios (ORs) with 95% confidence intervals (CIs), and heterogeneity was assessed with the I² statistic. For our MR analysis, we pooled genetic variants from selected studies and analyzed AD outcomes using IGAP, EADB, and UKB databases. Multiple MR methods, including inverse variance weighted (IVW) and pleiotropy–robust approaches, were applied for validation. Results: Of 271 articles, 8 MR studies were included (sample sizes: 68,905 to 788,989), all from European ancestry. Our meta-analysis found no significant causal link between T2DM and AD (OR = 1.02, 95% CI: 1.00–1.04) with moderate heterogeneity (I² = 31.3%). Similarly, our MR analysis using 512 SNPs as instrumental variables showed no significant associations in IGAP, EADB, or UKB data, which is consistent across sensitivity analyses. Conclusions: This meta-MR and MR analysis revealed no significant causal association between T2DM and AD, indicating that genetic predisposition to T2DM does not appear to causally influence AD risk, though modifiable clinical or environmental aspects of T2DM may still contribute to neurodegenerative processes. Further research should explore other mechanisms linking these conditions. Full article

(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))

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