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Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 12894

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Dr. Othmar Moser

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Guest Editor

Center of Sports Medicine & Sports Orthopedics, University Outpatient Clinic, University of Potsdam, Am Neuen Palais 12, 14469 Potsdam, Germany
Interests: diabetology; exercise; glucose metabolism
Special Issues, Collections and Topics in MDPI journals

Dr. Harald Sourij

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Guest Editor

Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
Interests: diabetology; exercise; glucose metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The aim of this Special Issue is to transfer existing knowledge of molecular mechanisms, obtained via clinical trials, to potential use in the routine care of people with diabetes, overweight, and obesity. In recent years, several novel glucose-lowering drugs have emerged; we do not yet fully understand their mechanisms of action and future roles in clinical treatment regimens. A close interplay between basic, translational, and clinical research is necessary to improve treatment options for people with diabetes, overweight, and obesity. In this context, we invite the submission of manuscripts concerning diabetes, overweight, and obesity. Topics may include but are not limited to

Beta cell function and treatment options for enhancing it;
The interplay of beta and alpha cells;
Treatment options for modulating peripheral and liver insulin sensitivity;
Glucose transporter (GLUT) modulation;
Novel mechanisms of action of glucose-lowering drugs;
Molecular mechanisms related to lifestyle interventions;
The pathophysiologic role of the gut microbiome and interventions for modulating the microbiome in metabolic diseases;
The role of inflammation in the treatment of diabetes and associated complications;
Novel molecules for the treatment of diabetes, overweight, and obesity;
The relationship between liver metabolism and diabetes.

Dr. Othmar Moser
Dr. Harald Sourij
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

diabetes mellitus
overweight
obesity
molecular mechanisms
microbiome
liver metabolism
advanced therapy

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Diabetes: From Molecular Mechanisms to Therapies Strategies in Biomolecules (3 articles)

Published Papers (7 papers)

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Research

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18 pages, 2276 KiB

Open AccessArticle

Inhibition of DPP-4 Attenuates Endotoxemia-Induced NLRC4 Inflammasome and Inflammation in Visceral Adipose Tissue of Mice Fed a High-Fat Diet

by Francesca Bianchi, Paola Roccabianca, Elena Vianello, Guendalina Gentile, Lucia La Sala, Francesco Bandera, Lorenza Tacchini, Riccardo Zoia, Massimiliano M. Corsi Romanelli and Elena Dozio

Biomolecules 2025, 15(3), 333; https://doi.org/10.3390/biom15030333 - 25 Feb 2025

Viewed by 1831

Abstract

Inflammasomes are protein complexes that trigger pro-inflammatory responses and promote many diseases, including adipose tissue dysfunction. Linagliptin (L), a DPP-4 inhibitor used for type 2 diabetes therapy, has putative anti-inflammatory effects. This work explores L effects on inflammasome regulation, inflammation, and adipose tissue dysfunction in obese mice. Male C57BL/6N mice were fed a normal chow (NC) diet, high-fat (HF) diet, or HF diet with L (HFL) for 15 weeks. Gene expression and histological examinations were performed on visceral (VAT) and subcutaneous (SAT) adipose tissue samples. Biomarkers were quantified on sera. Murine macrophages were utilized for in vitro analyses. L decreased HF-induced endotoxemia and circulating inflammatory indicators. Despite having no effect on body weight, L reduced VAT inflammation by decreasing endotoxemia-induced NLRC4 inflammasome, inflammation severity, and fat cell hypertrophy. Although SAT response differed from VAT, inflammation was slightly reduced in this tissue too. In vitro, L modulated inflammation by directly reducing the pro-inflammatory macrophage phenotype. In obesity, increased NLRC4 inflammasome expression links endotoxemia and VAT inflammation. L protected against endotoxemia, maybe by affecting gut permeability and VAT responses. The decreased polarization of macrophages toward a pro-inflammatory phenotype and the reduction in adipocyte hypertrophy are involved in the response to L. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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18 pages, 3924 KiB

Open AccessArticle

Diagnosis and Staging of Metabolic Dysfunction-Associated Steatotic Liver Disease Using Biomarker-Directed Aptamer Panels

by Mikkel B. Kjær, Asger G. Jørgensen, Søren Fjelstrup, Daniel M. Dupont, Claus Bus, Peter L. Eriksen, Karen L. Thomsen, Jeyanthini Risikesan, Søren Nielsen, Charlotte W. Wernberg, Mette M. Lauridsen, Elisabetta Bugianesi, Chiara Rosso, Henning Grønbæk and Jørgen Kjems

Biomolecules 2025, 15(2), 255; https://doi.org/10.3390/biom15020255 - 10 Feb 2025

Viewed by 851

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of adults globally. Despite efforts to develop non-invasive diagnostic tools, liver biopsy remains the gold standard for diagnosing metabolic dysfunction-associated steatohepatitis (MASH) and assessing fibrosis. This study investigated RNA aptamer panels, selected using APTASHAPE technology, for non-invasive MASLD diagnosis and fibrosis stratification. Aptamer panels were selected in a cohort of individuals with MASLD (development cohort, n = 77) and tested in separate cohorts: one with MASLD (test cohort, n = 57) and one assessed for bariatric surgery (bariatric cohort, n = 62). A panel distinguishing MASLD without steatohepatitis from MASH accurately stratified individuals in the developmentcohort (AUC = 0.83) but failed in the test and bariatric cohorts. It did, however, distinguish healthy controls from individuals with MASLD, achieving an AUC of 0.72 in the test cohort. A panel for fibrosis stratification differentiated F0 from F3–4 fibrosis in the development cohort (AUC = 0.68) but not in other cohorts. Mass spectrometry identified five plasma proteins as potential targets of the discriminative aptamers, with complement factor H suggested as a novel MASLD biomarker. In conclusion, APTASHAPE shows promise as a non-invasive tool for diagnosing and staging MASLD and identifying associated plasma biomarkers. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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9 pages, 442 KiB

Open AccessArticle

Serum Leucine-Rich Alpha-2 Glycoprotein 1 Levels in Patients with Lipodystrophy Syndromes

by Michelle Krienke, Susan Kralisch, Leonie Wagner, Anke Tönjes and Konstanze Miehle

Biomolecules 2024, 14(11), 1474; https://doi.org/10.3390/biom14111474 - 19 Nov 2024

Cited by 1 | Viewed by 1181

Abstract

Serum concentrations of leucine-rich alpha-2 glycoprotein 1 (LRG1) are elevated in several cardio-metabolic and inflammatory diseases. LRG1 also plays an important role in the development of hepatic steatosis and insulin resistance. In lipodystrophies (LDs), severe cardio-metabolic complications can be observed. The dysregulation of several adipokines plays a significant role in the clinical manifestation of this syndrome. To date, there have been no studies of LRG1 levels in non-HIV-LD patients. We performed a cross-sectional analysis of LRG1 serum levels in 60 patients with non-HIV-associated LD and in 60 age-, sex-, and BMI-matched healthy controls. Furthermore, we investigated the gene expression of Lrg1 in a mouse model of generalised LD. No significant difference was found in the median concentration of LRG1 serum levels between LD patients (18.2 ng/L; interquartile range 8.3 ng/L) and healthy controls (17.8 ng/L; interquartile range 11.0 ng/L). LRG1 serum concentrations correlated positively with CRP serum levels (p < 0.001). Lrg1 mRNA expression was downregulated in the adipose tissue, whereas in the liver, no difference in Lrg1 expression between LD and wild-type mice was detected. In summary, circulating levels of LRG1 are associated with low-grade inflammation but cannot distinguish between patients with LD and controls. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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16 pages, 1504 KiB

Open AccessArticle

Effect of a Concurrent Training Program with and Without Metformin Treatment on Metabolic Markers and Cardiorespiratory Fitness in Individuals with Insulin Resistance: A Retrospective Analysis

by Jairo Azócar-Gallardo, Alex Ojeda-Aravena, Eduardo Báez-San Martín, Tomás Herrera-Valenzuela, Marcelo Tuesta, Luis González-Rojas, Bibiana Calvo-Rico and José Manuel García-García

Biomolecules 2024, 14(11), 1470; https://doi.org/10.3390/biom14111470 - 19 Nov 2024

Cited by 2 | Viewed by 1806

Abstract

Background: Type 2 diabetes mellitus is a metabolic disorder characterized by insulin resistance (IR), which is prevalent worldwide and has significant adverse health effects. Metformin is commonly prescribed as a pharmacological treatment. Physical exercise is also recognized as an effective regulator of glycemia, independent of metformin. However, the effects of inter-day concurrent training (CT)—which includes both endurance and resistance exercises—combined with metformin treatment on metabolic markers and cardiorespiratory fitness in individuals with IR remain controversial. Objective: This study aimed to analyze the effects of a 12-week inter-day CT program on metabolic markers and cardiorespiratory fitness in overweight/obese individuals with IR, both with and without metformin treatment. Additionally, inter-individual responses to CT were examined. Materials and Methods: Data from the 2022–2023 Obesity Center database were retrospectively analyzed. According to the eligibility criteria, 20 overweight/obese individuals diagnosed with IR participated in a 12-week CT program (three weekly sessions: two endurance and one resistance exercise session). Participants were divided into three groups: the exercise group (E-G: n = 7, 32.86 ± 8.32 years, 85.2 ± 19.67 kg), the exercise–metformin group (E-MG: n = 6, 34.83 ± 12.91 years, 88.13 ± 12.66 kg), and the metformin-only control group (M-G: n = 7, 34.43 ± 13.96 years, 94.23 ± 13.93 kg). The M-G did not perform physical exercise during the 12 weeks but continued pharmacological treatment. Body composition, metabolic markers, and cardiorespiratory fitness were assessed before and after the 12-week CT program. Results: A group-by-time interaction was observed for fasting insulin (F_2,17 = 34.059, p < 0.001, η²_p = 0.88), the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (F_2,17 = 35.597, p < 0.001, η²_p = 0.80), and maximal fat oxidation (MFO) (F_2,17 = 4.541, p = 0.026, η²_p = 0.348) following the CT program. The maximal oxygen uptake (VO2_max) showed significant improvements in the E-G (F = 4.888, p = 0.041, ∆+13.3%). Additionally, the percentage of fat mass (%FM) and body mass (BM) were significantly reduced across all groups (F = 125.244, p < 0.001 and F = 91.130, p < 0.001, respectively). The BM decreased by ∆−9.43% in the E-G (five responders, Rs), ∆+9.21% in the EM-G (5 Rs), and ∆+5.15% in the M-G (3 Rs). The %FM was reduced in the E-G by ∆−22.52% (seven Rs). Fasting insulin and the HOMA-IR significantly improved in both the E-G and EM-G, with fasting insulin showing a ∆−82.1% reduction in the E-G (five Rs) and a ∆−85% reduction in the EM-G (six Rs). Similarly, the HOMA-IR improved by ∆+82.6% in the E-G (three Rs) and by ∆+84.6% in the EM-G (six Rs). Conclusions: The 12-week inter-day concurrent training program, whether combined with metformin or not, was similarly effective in improving metabolic markers in patients with insulin resistance as metformin treatment alone. Both exercise groups demonstrated a significant reduction in insulin sensitivity and an increase in maximal fat oxidation. Meanwhile, exclusive pharmacological treatment with metformin markedly decreased cardiorespiratory fitness, and consequently, fat oxidation. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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18 pages, 3144 KiB

Open AccessArticle

Effects of Interrupting Prolonged Sitting with Light-Intensity Physical Activity on Inflammatory and Cardiometabolic Risk Markers in Young Adults with Overweight and Obesity: Secondary Outcome Analyses of the SED-ACT Randomized Controlled Crossover Trial

by Sascha W. Hoffmann, Janis Schierbauer, Paul Zimmermann, Thomas Voit, Auguste Grothoff, Nadine B. Wachsmuth, Andreas Rössler, Tobias Niedrist, Helmut K. Lackner and Othmar Moser

Biomolecules 2024, 14(8), 1029; https://doi.org/10.3390/biom14081029 - 19 Aug 2024

Cited by 2 | Viewed by 2779

Abstract

Sedentary behavior (SB) is an essential risk factor for obesity, cardiovascular disease, and type 2 diabetes. Though certain levels of physical activity (PA) may attenuate the detrimental effects of SB, the inflammatory and cardiometabolic responses involved are still not fully understood. The focus of this secondary outcome analysis was to describe how light-intensity PA snacks (LIPASs, alternate sitting and standing, walking or standing continuously) compared with uninterrupted prolonged sitting affect inflammatory and cardiometabolic risk markers. Seventeen young adults with overweight and obesity participated in this study (eight females, 23.4 ± 3.3 years, body mass index (BMI) 29.7 ± 3.8 kg/m², glycated hemoglobin A1C (HbA_1c) 5.4 ± 0.3%, body fat 31.8 ± 8.2%). Participants were randomly assigned to the following conditions which were tested during an 8 h simulated workday: uninterrupted prolonged sitting (SIT), alternate sitting and standing (SIT-STAND, 2.5 h total standing time), continuous standing (STAND), and continuous walking (1.6 km/h; WALK). Each condition also included a standardized non-relativized breakfast and lunch. Venous blood samples were obtained in a fasted state at baseline (T₀), 1 h after lunch (T₁) and 8 h after baseline (T₂). Inflammatory and cardiometabolic risk markers included interleukin-6 (IL-6), c-reactive protein (CRP), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), visceral fat area (VFA), triglyceride-glucose (TyG) index, two lipid ratio measures, TG/HDL-C and TC/HDL-C, albumin, amylase (pancreatic), total protein, uric acid, and urea. We found significant changes in a broad range of certain inflammatory and cardiometabolic risk markers during the intervention phase for IL-6 (p = 0.014), TG (p = 0.012), TC (p = 0.017), HDL-C (p = 0.020), LDL-C (p = 0.021), albumin (p = 0.003), total protein (p = 0.021), and uric acid (p = 0.040) in favor of light-intensity walking compared with uninterrupted prolonged sitting, alternate sitting and standing, and continuous standing. We found no significant changes in CRP (p = 0.529), creatinine (p = 0.199), TyG (p = 0.331), and the lipid ratios TG/HDL-C (p = 0.793) and TC/HDL-C (p = 0.221) in response to the PA snack. During a simulated 8 h work environment replacement and interruption of prolonged sitting with light-intensity walking, significant positive effects on certain inflammatory and cardiometabolic risk markers were found in young adults with overweight and obesity. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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40 pages, 2330 KiB

Open AccessReview

Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM

by Shadi Bazzazzadehgan, Zia Shariat-Madar and Fakhri Mahdi

Biomolecules 2025, 15(3), 414; https://doi.org/10.3390/biom15030414 - 14 Mar 2025

Viewed by 908

Abstract

Type 2 diabetes mellitus (T2DM) encompasses a range of clinical manifestations, with uncontrolled diabetes leading to progressive or irreversible damage to various organs. Numerous genes associated with monogenic diabetes, exhibiting classical patterns of inheritance (autosomal dominant or recessive), have been identified. Additionally, genes involved in complex diabetes, which interact with environmental factors to trigger the disease, have also been discovered. These genetic findings have raised hopes that genetic testing could enhance diagnostics, disease surveillance, treatment selection, and family counseling. However, the accurate interpretation of genetic data remains a significant challenge, as variants may not always be definitively classified as either benign or pathogenic. Research to date, however, indicates that periodic reevaluation of genetic variants in diabetes has led to more consistent findings, with biases being steadily eliminated. This has improved the interpretation of variants across diverse ethnicities. Clinical studies suggest that genetic risk information may motivate patients to adopt behaviors that promote the prevention or management of T2DM. Given that the clinical features of certain monogenic diabetes types overlap with T2DM, and considering the significant role of genetic variants in diabetes, healthcare providers caring for prediabetic patients should consider genetic testing as part of the diagnostic process. This review summarizes current knowledge of the most common genetic variants associated with T2DM, explores novel therapeutic targets, and discusses recent advancements in the pharmaceutical management of uncontrolled T2DM. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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17 pages, 1616 KiB

Open AccessReview

Roles of Mitochondrial Dysfunction in Diabetic Kidney Disease: New Perspectives from Mechanism to Therapy

by Yichen Yang, Jiahui Liu, Qiling Shi, Buyu Guo, Hanbing Jia, Yuxuan Yang and Songbo Fu

Biomolecules 2024, 14(6), 733; https://doi.org/10.3390/biom14060733 - 20 Jun 2024

Cited by 3 | Viewed by 2657

Abstract

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and the main cause of end-stage renal disease around the world. Mitochondria are the main organelles responsible for producing energy in cells and are closely involved in maintaining normal organ function. Studies have found that a high-sugar environment can damage glomeruli and tubules and trigger mitochondrial dysfunction. Meanwhile, animal experiments have shown that DKD symptoms are alleviated when mitochondrial damage is targeted, suggesting that mitochondrial dysfunction is inextricably linked to the development of DKD. This article describes the mechanisms of mitochondrial dysfunction and the progression and onset of DKD. The relationship between DKD and mitochondrial dysfunction is discussed. At the same time, the progress of DKD treatment targeting mitochondrial dysfunction is summarized. We hope to provide new insights into the progress and treatment of DKD. Full article

(This article belongs to the Special Issue Diabetes, Overweight and Obesity: From Molecular Mechanisms to Therapies Strategies)

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