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Type 2 Diabetes: Molecular Pathophysiology and Treatment

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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: 20 September 2026 | Viewed by 14253

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Special Issue Editor

Dr. Edit Szabó

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Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Hungary
Interests: flow cytometry; membrane transporters; type 2 diabetes; gout; rheumatoid arthritis; genotyping; function and regulation of ABC membrane transporter proteins; red blood cells; immunometabolism

Special Issue Information

Dear Colleagues,

Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder affecting over 400 million individuals globally, characterized by hyperglycemia resulting from insulin resistance and/or relative insulin deficiency. Representing approximately 90% of all diabetes cases, T2DM is a multifactorial disease, influenced by genetic predisposition, lifestyle factors, hormonal imbalances, infections, and pharmacological agents. This complexity presents significant challenges in the accurate diagnosis and effective management of the disease. Prolonged T2DM increases the risk of serious complications, including cardiovascular disease, stroke, kidney failure, peripheral ischemia, and retinopathy, while the presence of comorbid conditions further exacerbates the burden on patients.

This Special Issue aims to compile cutting-edge original research and review articles exploring the bioinformatics, molecular, genetic, and immunological mechanisms underlying T2DM pathogenesis, as well as their potential as predictive, preventive, and prognostic markers. Additionally, this Special Issue invites research and review articles that present state-of-the-art advancements in therapeutic approaches for T2DM, highlighting innovative treatments and emerging strategies aimed at improving disease management and patient outcomes.

Dr. Edit Szabó
Guest Editor

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Keywords

type 2 diabetes mellitus and comorbidity
bioinformatics
molecular pathways
genetic background
biomarkers
novel therapies

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Published Papers (5 papers)

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Research

32 pages, 6395 KB

Open AccessArticle

Multi-Omics Analysis of a Spontaneous Type 2 Diabetes Model in Myodes rufocanus and Its Underlying Mechanisms

by Ijaz Ullah, Haseena Mujeeb, Qindan Li, Xingxuan Zhou, Habib Alam, Mujeeb Ur Rahman, Yanan Zhao, Jiazheng Zhou, Qingying Wang, Sanpin Luo, Liang Wang and Jingyu Wang

Int. J. Mol. Sci. 2026, 27(3), 1539; https://doi.org/10.3390/ijms27031539 - 4 Feb 2026

Viewed by 829

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia, progressive β-cell dysfunction, and insulin resistance. While numerous chemically induced and transgenic rodent models exist, spontaneous models recapitulating natural type 2 diabetes mellitus (T2DM) progression remain scarce. Here, we characterize Myodes rufocanus as a novel spontaneous T2DM model through comprehensive assessments of 18-week-old male F6 voles, demonstrating hallmark diabetic features including weight gain, hyperphagia, polydipsia, hyperglycemia, insulin resistance, and dyslipidemia. Pancreatic transcriptomic profiling revealed pronounced COX14 (cytochrome c oxidase assembly factor 14) downregulation, as validated by qPCR and Western blotting in pancreatic tissue and MIN6 β-cells. MIN6 cells under chronic high-glucose conditions (30 mM) exhibited diminished mitochondrial membrane potential, impaired ATP biosynthesis, elevated reactive oxygen species, and attenuated glucose-stimulated insulin secretion, with consistent COX14 downregulation suggesting potential association with mitochondrial dysfunction. Additionally, suppressed Nrf2–HO-1 antioxidant signaling appeared to compound cellular injury, with intrinsic apoptotic pathway activation indicated by elevated Bax/Bcl-2 ratios and caspase-3 activity. These findings establish M. rufocanus as a valuable spontaneous T2DM model and implicate COX14 downregulation as a potential correlate of mitochondrial impairment and β-cell failure in diabetes pathogenesis. Full article

(This article belongs to the Special Issue Type 2 Diabetes: Molecular Pathophysiology and Treatment)

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19 pages, 2182 KB

Open AccessArticle

Gut Microbiota and Type 2 Diabetes: Genetic Associations, Biological Mechanisms, Drug Repurposing, and Diagnostic Modeling

by Xinqi Jin, Xuanyi Chen, Heshan Chen and Xiaojuan Hong

Int. J. Mol. Sci. 2026, 27(2), 1070; https://doi.org/10.3390/ijms27021070 - 21 Jan 2026

Viewed by 1032

Abstract

Gut microbiota is a potential therapeutic target for type 2 diabetes (T2D), but its role remains unclear. Investigating causal associations between them could further our understanding of their biological and clinical significance. A two-sample Mendelian randomization (MR) analysis was conducted to assess the causal relationship between gut microbiota and T2D. Key genes and mechanisms were identified through the integration of Genome-Wide Association Studies (GWAS) and cis-expression quantitative trait loci (cis-eQTL) data. Network pharmacology was applied to identify potential drugs and targets. Additionally, gut microbiota community analysis and machine learning models were used to construct a diagnostic model for T2D. MR analysis identified 17 gut microbiota taxa associated with T2D, with three showing significant associations: Actinomyces (odds ratio [OR] = 1.106; 95% confidence interval [CI]: 1.06–1.15; p < 0.01; adjusted p-value [p_adj] = 0.0003), Ruminococcaceae (UCG010 group) (OR = 0.897; 95% CI: 0.85–0.95; p < 0.01; p_adj = 0.018), and Deltaproteobacteria (OR = 1.072; 95% CI: 1.03–1.12; p < 0.01; p_adj = 0.029). Ten key genes, such as EXOC4 and IGF1R, were linked to T2D risk. Network pharmacology identified INSR and ESR1 as target driver genes, with drugs like Dienestrol showing promise. Gut microbiota analysis revealed reduced α-diversity in T2D patients (p < 0.05), and β-diversity showed microbial community differences (R² = 0.012, p = 0.001). Furthermore, molecular docking confirmed the binding affinity of potential therapeutic agents to their targets. Finally, we developed a class-weight optimized Extreme Gradient Boosting (XGBoost) diagnostic model, which achieved an area under the curve (AUC) of 0.84 with balanced sensitivity (95.1%) and specificity (83.8%). Integrating machine learning predictions with MR causal inference highlighted Bacteroides as a key biomarker. Our findings elucidate the gut microbiota-T2D causal axis, identify therapeutic targets, and provide a robust tool for precision diagnosis. Full article

(This article belongs to the Special Issue Type 2 Diabetes: Molecular Pathophysiology and Treatment)

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15 pages, 2443 KB

Open AccessArticle

Bone Microstructural Deterioration and miR-155/RHOA-Mediated Osteoclastogenesis in Type 2 Diabetes Mellitus

by Mouza M. Alaleeli, Suneesh Kaimala, Ernest Adeghate and Sahar Mohsin

Int. J. Mol. Sci. 2025, 26(17), 8159; https://doi.org/10.3390/ijms26178159 - 22 Aug 2025

Viewed by 2047

Abstract

Type 2 diabetes mellitus (T2DM) is known to increase the risk of fragility fractures; however, the underlying mechanism is still elusive. Reduced miR-155 and elevated RHOA are known to drive bone resorption, but their role in T2DM remains unclear. This study investigates bone remodeling imbalances in T2DM through miR-155 and RHOA expression profiling. Three-month-old female Wistar rats were fed a high-calorie diet for 3 weeks, followed by intraperitoneal injections of two lower doses of streptozotocin at weekly intervals to induce T2DM. Bone analysis from diabetic rats tested using qRT-PCR showed significantly reduced miR-155 levels and elevated RHOA. Histological analysis showed a 12.65% increase in Tb.Sp, 10.07% decrease in Tb.Th, and significant increase (p < 0.05) in apoptotic osteocytes. The bone turnover marker CTx-1 level was increased by 20.84%, and RANKL levels were significantly increased in T2DM. IL-1β and TNF-α were increased in T2DM. Bone resorption is more likely to occur in T2DM as both IL-1β and TNF-α work synergistically to promote osteoclastogenesis. MiR-155 could be an important modulator of bone remodeling in T2DM and a potential therapeutic target for diabetic osteopathy. Full article

(This article belongs to the Special Issue Type 2 Diabetes: Molecular Pathophysiology and Treatment)

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17 pages, 995 KB

Open AccessArticle

Semaglutide Improves Lipid Subfraction Profiles in Type 2 Diabetes: Insights from a One-Year Follow-Up Study

by László Imre Tóth, Adrienn Harsányi, Sára Csiha, Ágnes Molnár, Hajnalka Lőrincz, Attila Csaba Nagy, György Paragh, Mariann Harangi and Ferenc Sztanek

Int. J. Mol. Sci. 2025, 26(13), 5951; https://doi.org/10.3390/ijms26135951 - 20 Jun 2025

Cited by 5 | Viewed by 6672

Abstract

Recent studies have demonstrated the efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in enhancing glycemic control, regulating body weight, and modulating lipid metabolism. However, their effects on lipoprotein subfractions have not been clarified. The objective of this 52-week, single-center, randomized trial was to compare the effects of subcutaneous semaglutide administered once weekly and oral sitagliptin administered once daily on anthropometric measurements and lipoprotein subfractions measured by Lipoprint gelelectrophoresis in patients with type 2 diabetes mellitus (T2DM). A total of 34 obese individuals with T2DM were enrolled in the study and randomly assigned to receive semaglutide (n = 18) or sitagliptin (n = 16). Thirty-one age- and body weight-matched non-diabetic obese individuals served as controls. Semaglutide treatment resulted in significant reductions in body mass index (BMI), waist circumference, and Hb_A1c, along with improvements in lipid parameters, including reductions in LDL cholesterol and non-HDL cholesterol levels, and redistribution of LDL and HDL subfractions toward a less atherogenic profile. Conversely, sitagliptin elicited modest glycemic improvements without substantial alterations in lipid composition. Multivariate regression analysis demonstrated that fluctuations in lipoprotein subfractions were not influenced by changes in BMI or HbA1c. These results support the pleiotropic metabolic benefits of semaglutide and its potential role in managing the cardiometabolic risk of T2DM. Full article

(This article belongs to the Special Issue Type 2 Diabetes: Molecular Pathophysiology and Treatment)

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17 pages, 1969 KB

Open AccessArticle

Genetic Variants of the Human Thiamine Transporter (SLC19A3, THTR2)—Potential Relevance in Metabolic Diseases

by Edit Szabó, Márton Pálinkás, Balázs Bohár, Botond Literáti-Nagy, László Korányi, Gyula Poór, György Várady and Balázs Sarkadi

Int. J. Mol. Sci. 2025, 26(7), 2972; https://doi.org/10.3390/ijms26072972 - 25 Mar 2025

Cited by 1 | Viewed by 2673

Abstract

Thiamine, crucial for energy metabolism, is associated with various human diseases when deficient. We studied how variations in the SLC19A3 gene, encoding THTR2, a thiamine transporter, may influence type 2 diabetes (T2DM) and gout (arthritis urica, AU). We characterized the SLC19A3 gene variants using bioinformatics and analyzed DNA samples from controls, T2DM, and gout patients to explore associations with physical/laboratory parameters. In human cells, we used a luciferase reporter assay to assess how these variants affect gene expression. We examined four large haplotypes (H1–4) in this gene, identified lead SNPs for the minor variants (MV), and explored potential transcription factor binding sites. We found that in T2DM patients, H3-MV correlated significantly with impaired glucose metabolism (pHOMA = 0.0189, pHbA1c% = 0.0102), while H4-MV correlated with altered uric acid (p = 0.0008) and white blood cell levels (p = 0.0272). In AU patients, H3-MV correlated with increased basophil granulocyte levels (p = 0.0273). In model cell lines, H3-MV presence increased gene expression (p = 0.0351), influencing responses to thiamine depletion and metformin (p = 0.0016). Although H4-MV did not directly affect luciferase expression, thiamine and fedratinib co-treatment significantly enhanced gene expression in thiamine-depleted cells (p = 0.04854). Our results suggest a connection between selected SLC19A3 variants and the severity of metabolic diseases or their response to treatment. Full article

(This article belongs to the Special Issue Type 2 Diabetes: Molecular Pathophysiology and Treatment)

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