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Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 April 2026) | Viewed by 18288

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Prof. Dr. Mihail Virgil Boldeanu

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Department of Immunology-Laboratory of Immunology, Universitatea de Medicina si Farmacie din Craiova, Craova, Romania
Interests: immunity; endocrine; chronic diseases; inflammatory bowel diesel; diabetes melitus; preeclampsia
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Dear Colleagues,

In recent years, several studies conducted among different populations, as well as on mice, have revealed new knowledge about the role of neurotransmission and inflammation in type 2 diabetes mellitus (T2DM) that is not currently included in protocols.

Thus, a more solid functional link between these neurotransmitters and markers of inflammation must be established. To better understand and describe this complex association, further large-scale studies among different patient groups are needed.

Epidemiological studies have established an association between inflammatory molecular biomarkers and the occurrence of T2DM and its complications. Because fat cells, macrophages, and other immune cells in the expanding adipose tissue interact with each other, it seems that adipose tissue is a major source of these molecular biomarkers. The identification of key molecular triggers of inflammation in T2DM is still poorly understood. The inflammatory response probably plays a part in the development of T2DM by making insulin less effective. This is made worse when hyperglycemia is present, which makes diabetes complications worse over time. Targeting inflammatory molecular pathways could be a component of strategies to prevent and control diabetes and its associated complications.

Serotonin, released by intestinal enterochromaffin cells, appears to regulate energy homeostasis through peripheral mechanisms. Serotonergic effects on energy balance lead to secondary effects on glucose homeostasis, based on a well-established link between obesity and insulin resistance.

This Special Issue invites research papers that highlight the involved DM molecular markers and pathways and outline perspectives for personalized DM diagnosis and treatment. Systemizing reviews on these topics are also welcome.

Dr. Mihail Virgil Boldeanu
Guest Editor

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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.

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Keywords

metabolic disorders
diabetes mellitus
inflammation
neurotransmitter
inflammatory biomarkers
molecular target
molecular diagnostics
therapeutics
insulin resistance

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Research

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28 pages, 1539 KB

Open AccessArticle

Circulating Adiponectin and Omentin Across Cardiometabolic Phenotypes: Links to Atherogenic Indices in Prediabetes and New-Onset Type 2 Diabetes

by Daniela Denisa Mitroi Sakizlian, Daniela Ciobanu, Lidia Boldeanu, Mohamed-Zakaria Assani, Isabela Siloși, Vlad Pădureanu, Daniel Cosmin Caragea, Venera Cristina Dinescu and Alina Elena Ciobanu Plasiciuc

Int. J. Mol. Sci. 2026, 27(6), 2558; https://doi.org/10.3390/ijms27062558 - 11 Mar 2026

Viewed by 521

Abstract

Adiponectin and omentin are adipose tissue-derived adipokines implicated in insulin sensitivity and cardiometabolic regulation. Their behavior across different stages of dysglycemia, as well as in relation to visceral adiposity and cardiometabolic phenotypes, remains incompletely understood. In this cross-sectional study, circulating adiponectin and omentin levels were evaluated in individuals with prediabetes (PreDM, n = 100) and newly diagnosed type 2 diabetes mellitus (T2DM, n = 128). Associations with insulin resistance-related indices, including the triglyceride–glucose (TyG) index and TyG-derived composites, the visceral adiposity index (VAI), cardiometabolic phenotypes, and cardiovascular risk categories, were assessed using correlation and multivariable regression analyses. Discriminatory performance for metabolically unhealthy obesity was evaluated using receiver operating characteristic (ROC) curve analysis. Both adiponectin and omentin levels were lower in T2DM compared with PreDM (22.05 vs. 30.30 and 25.72 vs. 38.84, p < 0.0001 for both). In PreDMs, omentin showed a significant inverse correlation with the TyG index (weak correlation, ρ = −0.197, p = 0.050), whereas adiponectin demonstrated only weak trends. In multivariable models, VAI and male sex were independent predictors of circulating omentin levels, whereas fasting insulin was not. In contrast, adiponectin did not retain independent associations with metabolic or visceral adiposity indices. In T2DM, adipokine–metabolic associations were largely absent. Neither adipokine differed substantially across cardiometabolic phenotypes or cardiovascular risk categories. ROC analyses revealed modest overall discriminatory performance for metabolically obese phenotypes, with poor discrimination after stratification by glycemic status (area under the ROC curve (AUC) of 0.704 for adiponectin and 0.710 for omentin, and AUC of 0.431 for adiponectin and 0.461 for omentin, respectively). Circulating adipokines appear to exhibit stage-dependent relationships with metabolic dysfunction, being more informative in PreDM than in established T2DM. Omentin may reflect visceral adiposity-related metabolic alterations in early dysglycemia, whereas adiponectin shows limited independent associations. Overall, these findings suggest that adipokines have limited diagnostic or cardiovascular risk-stratification utility when considered in isolation and may be better interpreted within multimarker cardiometabolic assessment frameworks. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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19 pages, 1386 KB

Open AccessArticle

Comparison of Severe COVID-19 Outcomes in Vaccinated and Unvaccinated Patients, with and Without Diabetes Mellitus in a Romanian Tertiary Healthcare Pneumology Hospital—A Retrospective Study

by Ioana-Mădălina Moşteanu, Adela Gabriela Ştefan, Beatrice Mahler, Adina Mitrea, Ionela Mihaela Vladu, Oana-Andreea Parliţeanu, Diana Clenciu, Eugen Moţa, Maria Magdalena Roşu, Delia-Viola Reurean Pintilei, Beatrice Elena Vladu, Alexandru Stoichiță, Diana Cristina Protasiewicz-Timofticiuc, Theodora Claudia Radu-Gheonea, Ion-Cristian Efrem, Anca Maria Amzolini and Maria Moţa

Int. J. Mol. Sci. 2026, 27(4), 2082; https://doi.org/10.3390/ijms27042082 - 23 Feb 2026

Viewed by 712

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on public health. In the present study, we aimed to analyze the association of certain inflammatory biomarkers with severe COVID-19 and to explore the role of diabetes mellitus (DM) and vaccination status in relation to COVID-19 severity, intensive care need and mortality. Associated comorbidities (DM, obesity, cardiovascular, neurological, endocrine, hepatic, renal, pulmonary, rheumatological, psychiatric, hematological diseases, cancer and HIV), as well as inflammatory biomarkers, like ferritin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were analyzed in 866 subjects, according to vaccination status. In unvaccinated subjects, the highest AUROC curve for severe COVID-19 was recorded for CRP (0.668), and in the vaccinated group, the highest was recorded for SII (0.694). In age- and comorbidity-adjusted analyses, diabetes mellitus was associated with higher odds of severe COVID-19, ICU admission, and mortality among unvaccinated patients. This analysis was not feasible in the vaccinated group because of the very low number of unfavorable outcomes. These findings emphasize the potential role of vaccination in attenuating the excess risk linked to comorbidities—particularly diabetes mellitus—and support the use of accessible inflammatory biomarkers for early risk stratification. The results should be interpreted within the specific epidemiological phases of the pandemic and in the context of the observational study design. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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32 pages, 1950 KB

Open AccessArticle

Association of Circulating Irisin with Insulin Resistance and Metabolic Risk Markers in Prediabetic and Newly Diagnosed Type 2 Diabetes Patients

by Daniela Denisa Mitroi Sakizlian, Lidia Boldeanu, Diana Clenciu, Adina Mitrea, Ionela Mihaela Vladu, Alina Elena Ciobanu Plasiciuc, Mohamed-Zakaria Assani and Daniela Ciobanu

Int. J. Mol. Sci. 2026, 27(2), 787; https://doi.org/10.3390/ijms27020787 - 13 Jan 2026

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Circulating irisin, a myokine implicated in energy expenditure and adipose tissue regulation, has been increasingly studied as a potential biomarker of metabolic dysfunction. This study evaluated the relationship between serum irisin and metabolic indices, including the atherogenic index of plasma (AIP), the lipid accumulation product (LAP), and hypertriglyceridemic-waist (HTGW) phenotype in individuals with prediabetes (PreDM) and newly diagnosed type 2 diabetes mellitus (T2DM). A total of 138 participants (48 PreDM, 90 T2DM) were assessed for anthropometric, glycemic, and lipid parameters. Serum irisin levels were measured by enzyme-linked immunosorbent assay (ELISA) and correlated with insulin resistance indices (Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (QUICKI)), glycemic control (glycosylated hemoglobin A1c (HbA1c)), and composite lipid markers (total triglycerides-to-high-density lipoprotein cholesterol (TG/HDL-C)). Group differences were evaluated using non-parametric tests; two-way ANOVA assessed interactions between phenotypes and markers; multiple linear regression (MLR) and logistic regression models explored independent associations with metabolic indices and HTGW; receiver operating characteristic (ROC) analyses compared global and stratified model performance. Serum irisin was significantly lower in T2DM than in PreDM (median 140.4 vs. 230.7 ng/mL, p < 0.0001). Irisin levels remained comparable between males and females in both groups. Post hoc analysis shows that lipid indices and irisin primarily distinguish HTGW phenotypes, especially in T2DM. In both groups, irisin correlated inversely with HOMA-IR, AIP, and TG/HDL-C, and positively with QUICKI, indicating a possible compensatory role in early insulin resistance. MLR analyses revealed no independent relationship between irisin and either AIP or LAP in PreDM, while in T2DM, waist circumference remained the strongest negative predictor of irisin. Logistic regression identified age, male sex, and HbA1c as independent predictors of the HTGW phenotype, while irisin contributed modestly to overall model discrimination. ROC curves demonstrated good discriminative performance (AUC = 0.806 for global; 0.794 for PreDM; 0.813 for T2DM), suggesting comparable predictive accuracy across glycemic stages. In conclusion, irisin levels decline from prediabetes to overt diabetes and are inversely linked to lipid accumulation and insulin resistance but do not independently predict the HTGW phenotype. These findings support irisin’s role as an integrative indicator of metabolic stress rather than a stand-alone biomarker. Incorporating irisin into multi-parameter metabolic panels may enhance early detection of cardiometabolic risk in dysglycemic populations. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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16 pages, 622 KB

Open AccessArticle

A Composite Score of Insulin Resistance and Inflammation Biomarkers for Predicting Lower Limb Complications in Type 2 Diabetes Mellitus

by Adina Mitrea, Adela-Gabriela Ștefan, Ionela-Mihaela Vladu, Diana Clenciu, Sorina-Ionelia Stan, Ion-Cristian Efrem, Viorel Biciușcă, Moța Maria, Diana-Cristina Protasiewicz-Timofticiuc, Maria-Magdalena Roșu, Theodora-Claudia Radu-Gheonea, Eugen Moța, Gabriel Mogoș, Delia-Viola Reurean-Pintilei, Lidia Boldeanu and Tiberiu-Ștefăniță Țenea-Cojan

Int. J. Mol. Sci. 2025, 26(24), 11859; https://doi.org/10.3390/ijms262411859 - 9 Dec 2025

Cited by 1 | Viewed by 975

Abstract

Diabetes mellitus (DM) is a chronic non-communicable disease associated with macroangiopathy and microangiopathy, with disabling or even life-threatening complications. In the present study, we aimed to analyze the association between insulin resistance (IR) and inflammation biomarkers and peripheral arterial disease (PAD) and diabetic peripheral neuropathy (DPN), respectively. The study had a cross-sectional design and evaluated a panel of IR related indices and inflammatory biomarkers commonly used in clinical and epidemiological research, including the triglyceride-glucose (TyG) index and its obesity related derivates, cholesterol, HDL, glucose (CHG) index, lipid-derived ratios, and composite inflammatory indices, together with interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα) and C-reactive protein (CRP) in 110 subjects, according to the presence or absence of PAD and DPN, respectively. In the PAD (+) group, TyG-waist-to-height-ratio (TyG−WHtR) and CHG recorded significantly increased values (p = 0.042, respectively p < 0.001), compared to PAD (−). CHG recorded significantly increased values in DPN (+) subjects (p = 0.007). In addition, in the PAD (+) subjects, IL-6 and systemic immune inflammation index (SII) recorded significantly increased values (p = 0.026, respectively, p = 0.015) and TNFα, monocyte to lymphocyte ratio (MLR) and C-reactive protein to albumin ratio (CAR) recorded significantly increased values in DPN (+) subjects (p = 0.028, respectively, p = 0.008, and p = 0.038). We developed a score with a good discriminatory performance for PAD and DPN, including DM duration, TyG−WHtR, SII, MLR and CAR (AUROC 0.822 in PAD, respectively 0.848 in DPN, p < 0.001). A composite score combining IR and inflammatory biomarkers showed strong discriminatory performance for lower limb complications in type 2 diabetes, suggesting a valuable tool for early detection and prevention. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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26 pages, 967 KB

Open AccessArticle

Neurotransmitter Levels (Dopamine, Epinephrine, Norepinephrine, Serotonin) and Associations with Lipid Profiles in Patients with Prediabetes or Newly Diagnosed Type 2 Diabetes Mellitus

by Roxana Viorela Ahrițculesei, Lidia Boldeanu, Mohamed-Zakaria Assani, Adina Mitrea, Cosmin Vasile Obleaga, Ionela Mihaela Vladu, Diana Clenciu, Mihail Virgil Boldeanu and Cristin Constantin Vere

Int. J. Mol. Sci. 2025, 26(20), 10068; https://doi.org/10.3390/ijms262010068 - 16 Oct 2025

Cited by 2 | Viewed by 2208

Abstract

Neurotransmitters play a pivotal role not only in central nervous system signaling but also in the regulation of systemic energy metabolism, insulin sensitivity, and cardiovascular function. The contribution of neuroendocrine dysregulation to the development of type 2 diabetes mellitus (T2DM) is increasingly being recognized; however, the interplay between neurotransmitter levels and lipid/insulin resistance profiles in T2DM and prediabetes (PreDM) remains poorly characterized. We evaluated serum dopamine (DA), norepinephrine (NE), epinephrine (EPI), and serotonin (ST) in 110 individuals with PreDM (n = 40) or newly diagnosed T2DM (n = 70). Extended metabolic profiling included HbA1c, lipid panels, and insulin resistance indices (triglyceride-to-glucose index (TyG), TyG-derived indices). Neurotransmitter levels were compared across body mass index (BMI) categories, gender, and glycosylated hemoglobin A1c (HbA1c) quartiles. We applied multivariable linear regression (MLR) adjusted for body mass index (BMI), age, sex, lipids, penalized logistic regression (predicting T2DM status), and exploratory Spearman correlations with False Discovery Rate (FDR) correction. All four neurotransmitters were significantly higher in T2DM versus PreDM (p < 0.001). In T2DM patients, DA and NE levels increased across HbA1c quartiles, and NE levels were significantly higher in quartile 3 compared to quartile 2 (p = 0.045). In multivariable models, T2DM status was the only consistent predictor of neurotransmitter elevations. Logistic regression identified ST (OR = 8.70) and NE (OR = 3.76) as key discriminators of T2DM status, in addition to HbA1c. Exploratory correlation analyses in T2DM showed trends between EPI and insulin resistance indices (TyG adjusted for waist circumference (TyG-WC), TyG adjusted for waist-to-height ratio (TyG-WHtR)) and between DA and low-density lipoprotein cholesterol (LDL-C), although these did not survive to FDR correction. Neurotransmitter levels are elevated in T2DM and correlate with glycemic and metabolic profiles, suggesting early neuroendocrine involvement in the pathogenesis of diabetes. Serotonin and norepinephrine may serve as adjunctive biomarkers for disease stratification, meriting further prospective and mechanistic investigation. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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21 pages, 1551 KB

Open AccessArticle

Relationship Between Insulin Resistance Indicators and Type 2 Diabetes Mellitus in Romania

by Adela-Gabriela Ştefan, Diana Clenciu, Ionela-Mihaela Vladu, Adina Mitrea, Diana-Cristina Protasiewicz-Timofticiuc, Maria-Magdalena Roşu, Theodora-Claudia Gheonea, Beatrice-Elena Vladu, Ion-Cristian Efrem, Delia-Viola Reurean Pintilei, Eugen Moţa and Maria Moţa

Int. J. Mol. Sci. 2025, 26(20), 9888; https://doi.org/10.3390/ijms26209888 - 11 Oct 2025

Cited by 5 | Viewed by 2202

Abstract

Diabetes mellitus (DM) is a complex chronic disease, with a prevalence that has reached alarming proportions in recent decades. In this study, we aimed to analyze the association of type 2 diabetes mellitus (T2DM) with certain insulin resistance (IR) indicators, according to the gender of the participants enrolled in the PREDATORR study. Biomarkers such as the triglyceride–glucose (TyG) index and its derivates, triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-c), and metabolic score for insulin resistance (METS-IR), as well as recent indicators, like cholesterol, HDL, the glucose (CHG) index and its derivates, CHG–body mass index (CHG-BMI), and CHG–waist circumference (CHG-WC), as well as its newly proposed derivates, such as CHG–waist-to-height ratio (CHG-WHtR), CHG–neck circumference (CHG-NC), and CHG–neck-to-height ratio (NHtRs were analyzed in 2080 subjects, divided into two groups, according to gender). Univariate and multivariate logistic regression was used to identify the relationships between IR indicators and T2DM. Regardless of gender, all the analyzed indicators presented statistically significantly higher values in T2DM (+) compared to T2DM (−). For both studied groups, CHG–WHtR had the largest AUROC curve: in males, the AUROC curve was 0.809, the cut-off value being 3.22, with a 70.7% sensitivity and 75.3% specificity; in females, the AUROC curve was 0.840, the cut-off value was 3.20, with a 79.3% sensitivity and 75.5% specificity, respectively. Regardless of gender, the age-adjusted model for multivariate logistic regression analysis demonstrated that TyG and CHG were predictive factors for T2DM. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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13 pages, 239 KB

Open AccessArticle

Improvement in Glucometric Outcomes After Control-IQ Initiation in Pediatric and Adolescent Type 1 Diabetes Patients: The Impact of Basal Time in Range

by Ana Gómez-Perea, Alfonso Lendínez-Jurado, Silvia Gallego-Gutiérrez, Fuensanta Guerrero-Del-Cueto, Ana García-Ruiz, Cristina López-De La Torre, Fernando Cardona-Díaz and Isabel Leiva-Gea

Int. J. Mol. Sci. 2025, 26(19), 9638; https://doi.org/10.3390/ijms26199638 - 2 Oct 2025

Cited by 1 | Viewed by 1700

Abstract

The development of closed-loop systems represents an evolutionary advance in the management of patients with type 1 diabetes (T1D). This study aimed to analyze the impact of the Control-IQ advanced hybrid closed-loop (AHCL) system on glucometric outcomes in a pediatric and adolescent population with T1D, comparing results with baseline values and assessing the influence of baseline Time in Range (TIR) on glycemic control in children under 6 years old over a 12-month period. A 12-month prospective analysis was conducted in 26 patients with T1D (aged 2–15 years) initiating the Control-IQ system. Glucometric variables were assessed at baseline (before system implementation) and at 1, 3, 6, and 12 months post-implementation. A subgroup analysis was performed in patients under 6 years old (n = 13), to evaluate the relationship between basal TIR and glucometric outcomes during the follow-up. TIR increased significantly from 62.04% at baseline to 72.50% at one month (from 57.58% to 66.18% in patients under 6 years), with this improvement sustained throughout follow-up. Time in hyperglycemia 180–250 mg/dL (TAR1) also showed significant improvement (26.84% to 17.40% at one month; 28.66% to 20.09% in patients under 6 years), with significant reductions maintained at all timepoints. Stratification according to the proportion of patients meeting consensus targets revealed significant improvements in TIR and TAR2 at 1 and 12 months in the overall cohort, though not in the under-6 subgroup. Significant differences in TIR and coefficient of variation (CV) were observed based on baseline TIR categorization (<70% vs. ≥70%). Our study revealed a significant enhancement in TIR and time spent in hyperglycemia from the first month after the implementation of the closed-loop system, which was maintained at 12 months, in both the overall cohort and the subgroup under 6 years old. In this younger subgroup, baseline TIR predicted subsequent glycemic control, with higher baseline TIR associated with better long-term outcomes in both TIR and CV. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

12 pages, 1831 KB

Open AccessArticle

Serum Vitamin D Levels as Predictors of Response to Intravitreal Anti-VEGF Therapy in Diabetic Macular Edema: A Clinical Correlation Study

by Nejla Dervis, Sanda Jurja, Tatiana Chisnoiu, Cristina Maria Mihai and Ana Maria Stoica

Int. J. Mol. Sci. 2025, 26(17), 8481; https://doi.org/10.3390/ijms26178481 - 1 Sep 2025

Viewed by 1151

Abstract

Our study explored the role of serum 25-hydroxyvitamin D [25(OH)D] levels as an indicator of response to intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy in patients with diabetic macular edema (DME), highlighting functional and anatomical outcomes linked to systemic biomarker profiles. In a cohort of treatment-naive diabetic patients, vitamin D status was correlated with post-treatment changes in central macular thickness (CMT) and best-corrected visual acuity (BCVA), illustrating layered therapeutic responses among deficient, insufficient, and sufficient vitamin D groups. Functional gains, measured as improvements in decimal BCVA, and anatomical improvements, defined by CMT reduction via spectral-domain optical coherence tomography (SD-OCT), were primarily detected in patients with sufficient vitamin D levels. Remarkably, patients with serum 25(OH)D ≥ 30 ng/mL revealed complete dual-response rates, while those in the deficient group manifested partial therapeutic efficacy, supporting the immunoangiogenic modulatory role of vitamin D. Statistical associations exposed a tight linear connection between baseline and final visual acuity and a pronounced inverse relationship between CMT and final vision, suggesting that vitamin D may play a role in treatment-mediated structural recovery. These results may imply that low vitamin D levels lead to subclinical endothelial dysfunction and impaired retinal barrier repair, possibly through dysregulated anti–vascular endothelial growth factor (anti-VEGF) signaling, chronic inflammation, and oxidative stress. Our findings underscore the need for and importance of further research of vitamin D status as an adjunctive biomarker in the clinical approach of personalized DME and validates the potential of circulating vitamin D evaluation in therapeutic classification and predictive eye care. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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Review

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15 pages, 585 KB

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Diabetes Mellitus and COVID-19 in Adults: A Systematic Review of Pathophysiological Connections, Clinical Outcomes, and Therapeutic Considerations

by Ioana-Madalina Mosteanu, Oana-Andreea Parliteanu, Beatrice Mahler, Adina Mitrea, Diana Clenciu, Adela Gabriela Stefan, Diana Cristina Protasiewicz Timofticiuc, Alexandru Stoichita, Mihaela Simona Popoviciu, Delia Viola Reurean Pintilei, Maria Magdalena Rosu, Theodora Claudia Radu Gheonea, Beatrice Elena Vladu, Lidia Boldeanu, Eugen Mota, Ion Cristian Efrem, Ionela Mihaela Vladu and Maria Mota

Int. J. Mol. Sci. 2026, 27(8), 3537; https://doi.org/10.3390/ijms27083537 - 15 Apr 2026

Viewed by 439

Abstract

The disproportionately severe disease course of diabetic patients with SARS-CoV-2 infection was repeatedly observed by clinicians during the COVID-19 pandemic. The overlap between metabolic impairment, viral pathophysiology, and chronic inflammation created a pattern that urged deeper examination. The aim of this paper was to review and synthesize evidence regarding the interaction between diabetes mellitus and COVID-19. We synthesized evidence across mechanistic pathways (immune dysregulation, chronic inflammation, ACE2/DPP-4-related signaling, endothelial dysfunction, and pancreatic involvement) and key clinical outcomes (severity, intensive care unit (ICU) admission, mortality, dysglycaemia/new-onset diabetes, and DKA). This systematic search was conducted in PubMed, Clinical Key, and Google Scholar. The eligibility criteria included papers on adults (≥18 years) with pre-existing diabetes mellitus (type 1 or type 2) or newly diagnosed diabetes/hyperglycemia and confirmed SARS-CoV-2 infection, published between January 2020 and October 2025, in English language. The PRISMA guidelines were used for data extraction. We identified 412 articles, out of which only 30 met all the inclusion criteria. Diabetes was consistently evoked as a major risk factor for severe COVID-19, being associated with higher susceptibility to pneumonia, respiratory failure, ICU admission, and mortality. The explanation lies in the impaired immune system, endothelial dysfunction, and metabolic repercussions imposed by hyperglycemia. Several antidiabetic drugs appeared protective in multiple cohorts. In conclusion, the accumulated evidence underscores the tight interplay between metabolic disease and COVID-19. Essentially, the clinical management of these patients would be a thoughtful selection of antidiabetic therapy and close metabolic monitoring. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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18 pages, 775 KB

Open AccessReview

Orforglipron: A Comprehensive Review of an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity and Type 2 Diabetes

by Urna Kansakar, Stanislovas S. Jankauskas, Shivangi Pande, Pasquale Mone, Fahimeh Varzideh and Gaetano Santulli

Int. J. Mol. Sci. 2026, 27(3), 1409; https://doi.org/10.3390/ijms27031409 - 30 Jan 2026

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Abstract

Orforglipron (LY3502970) is a novel, orally available, nonpeptide glucagon-like peptide-1 receptor agonist (GLP-1 RA) designed to replicate the efficacy of injectable GLP-1 RAs for glycemic control and weight reduction while improving convenience and adherence. Preclinical studies have demonstrated potent receptor engagement, favorable pharmacokinetics, and central nervous system activity. Phase 1–3 clinical trials have shown significant reductions in glycated hemoglobin (HbA1c), fasting and postprandial glucose, body weight, and cardiovascular risk biomarkers, with an acceptable safety profile. This comprehensive review integrates pharmacological, clinical, and mechanistic evidence, critically evaluates the data, identifies knowledge gaps, and outlines future directions for orforglipron in the treatment of type 2 diabetes and obesity. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)

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