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Molecular Diagnosis and Treatments of Diabetes Mellitus

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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 January 2025) | Viewed by 13205

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Dr. Mihail Virgil Boldeanu

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Department of Immunology, University of Medicine and Pharmacy, 200349 Craiova, Romania
Interests: pancreatic disorders; polymorphism; genotype; VEGFR-2; vitamin C; ascorbic acid; diabetes mellitus; periodontal disease; antigens; monoclonal antibody; NLRP3; citokines; pro-angiogenic factors; chronic periodontitis; case-control; matrix metalloproteinase; periodontal pa-rameters
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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 leads to secondary effects on glucose homeostasis, based on a well-established link between obesity and insulin resistance.

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

Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition in International Journal of Molecular Sciences

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29 pages, 10404 KiB

Open AccessArticle

Association Between Pentraxins and Obesity in Prediabetes and Newly Diagnosed Type 2 Diabetes Mellitus Patients

by Roxana-Viorela Ahrițculesei, Lidia Boldeanu, Daniel Cosmin Caragea, Ionela Mihaela Vladu, Diana Clenciu, Adina Mitrea, Anca Marilena Ungureanu, Constantin-Cristian Văduva, Anda Lorena Dijmărescu, Alin Iulian Silviu Popescu, Mohamed-Zakaria Assani, Mihail Virgil Boldeanu and Cristin Constantin Vere

Int. J. Mol. Sci. 2025, 26(8), 3661; https://doi.org/10.3390/ijms26083661 - 12 Apr 2025

Viewed by 282

Abstract

Systemic inflammation has an important role in the prognosis and progression of many chronic diseases, including diabetes (T2DM). This retrospective study aimed to evaluate inflammatory status by determining the serum inflammatory biomarkers (PTX3, hs-CRP, TNF-α, and IL-6) and new indices, like the mean corpuscular volume (MCV) to lymphocyte ratio (MCVL) and cumulative inflammatory index (IIC), in a cohort of patients with prediabetes (PreDM) and newly diagnosed T2DM. We also wanted to assess the association with clinical parameters and different obesity-related indices, to identify possible correlations and to evaluate the diagnostic accuracy of the biomarkers using ROC curve analysis. In this study, we included 60 patients diagnosed with T2DM and 30 patients with PreDM. The ELISA method was applied. Elevated PTX3, hs-CRP, TNF-α, and IL-6 levels were found in T2DM patients compared to preDM patients. An independent relationship was found between PTX3, hs-CRP, and different obesity-related indices in patients with preDM and T2DM. The MCVL index exhibited an inverse trend proportional to the rising levels of HbA1c in the T2DM group. Spearman’s analysis revealed in the T2DM group that the PTX3 values correlated much better with IIC (rho = 0.445, p-value = 0.014) and MCVL (rho = 0.338, p-value = 0.048). Hs-CRP values expressed moderate-to-weak correlations with IIC and MCVL in both groups. Additionally, ROC analysis showed that the PTX3 (AUC was 0.720; p = 0.003; cut-off value 1888.00 pg/mL, with 67.60% sensitivity and 73.30% specificity) and MCVL index (AUC was 0.677; p = 0.047; cut-off value 39.60, with 63.30% sensitivity and 66.70% specificity) have a good, accurate diagnosis compared with IL-6 (AUC was 0.866; p < 0.0001; cut-off value 40.30 pg/mL, with 100.00% sensitivity and 60.00% specificity). IIC showed 61.70% sensitivity and 60.00% specificity, with an AUC of 0.572, p = 0.027 and a cut-off value of 2.35. PTX3 and MCVL can serve as independent predictor factors in the inflammatory status in preDM and T2DM patients, supporting their potential as biomarkers for T2DM management and future research. Full article

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

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15 pages, 2439 KiB

Open AccessArticle

Characterization of Anti-Insulin Antibodies in Type 1 and Type 2 Diabetes Mellitus: Clinical Relevance

by Henrik Toft-Hansen, Christina Aniol-Nielsen, Daniel Elias, Madeleine Dahlbäck, Peter Rossing, Suvanjaa Sivalingam, William A. Hagopian, Darius A. Schneider, Claus H. Nielsen and Helene Solberg

Int. J. Mol. Sci. 2025, 26(4), 1730; https://doi.org/10.3390/ijms26041730 - 18 Feb 2025

Viewed by 792

Abstract

The administration of insulin as a treatment for diabetes frequently leads to the formation of anti-insulin antibodies (IAs). The influence of these antibodies on the efficacy and safety of insulin therapy remains incompletely understood. This study presents a systematic, exploratory, cross-sectional analysis of the quantitative and qualitative properties of IAs in 101 patients with type 1 diabetes (T1D) and 101 patients with type 2 diabetes (T2D). The goal was to identify subpopulations of IAs that might impact glycemic control. We assessed the presence, titer, isotype, subclass, avidity, and in vitro neutralizing capacities of IAs, using glycated hemoglobin A1c (HbA1c) levels as an indicator of the clinical effectiveness of insulin. Our findings showed that 72% of individuals with T1D and 32% with T2D developed IAs, with IgG being the predominant isotype in both groups. Despite the presence of IAs, no in vitro neutralizing effect against insulin was observed, and there was no significant correlation between IA titer or avidity and HbA1c levels in either group. The results from this study demonstrate that while IAs are prevalent in both T1D and T2D, they do not have a significant clinical impact on the outcomes of insulin therapy in our study populations. Full article

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

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16 pages, 2518 KiB

Open AccessArticle

Redosing with Intralymphatic GAD-Alum in the Treatment of Type 1 Diabetes: The DIAGNODE-B Pilot Trial

by Rosaura Casas, Andrea Tompa, Karin Åkesson, Pedro F. Teixeira, Anton Lindqvist and Johnny Ludvigsson

Int. J. Mol. Sci. 2025, 26(1), 374; https://doi.org/10.3390/ijms26010374 - 4 Jan 2025

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Abstract

Immunotherapies aimed at preserving residual beta cell function in type 1 diabetes have been successful, although the effect has been limited, or raised safety concerns. Transient effects often observed may necessitate redosing to prolong the effect, although this is not always feasible or safe. Treatment with intralymphatic GAD-alum has been shown to be tolerable and safe in persons with type 1 diabetes and has shown significant efficacy to preserve C-peptide with associated clinical benefit in individuals with the human leukocyte antigen DR3DQ2 haplotype. To further explore the feasibility and advantages of redosing with intralymphatic GAD-alum, six participants who had previously received active treatment with intralymphatic GAD-alum and carried HLA DR3-DQ2 received one additional intralymphatic dose of 4 μg GAD-alum in the pilot trial DIAGNODE-B. The participants also received 2000 U/day vitamin D (Calciferol) supplementation for two months, starting one month prior to the GAD-alum injection. During the 12-month follow-up, residual beta cell function was estimated with Mixed-Meal Tolerance Tests, and clinical and immune responses were observed. C-peptide decreased minimally, and most patients showed stable HbA1c and IDAA1c. The mean % TIR increased while the mean daily insulin dose decreased at month 12 compared to the baseline. Redosing with GAD-alum seems to be safe and tolerable, and may prolong the disease modification elicited by the original GAD-alum treatment. Full article

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

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14 pages, 1279 KiB

Open AccessArticle

Kallistatin as a Potential Marker of Therapeutic Response During Alpha-Lipoic Acid Treatment in Diabetic Patients with Sensorimotor Polyneuropathy

by Marcell Hernyák, László Imre Tóth, Sára Csiha, Ágnes Molnár, Hajnalka Lőrincz, György Paragh, Mariann Harangi and Ferenc Sztanek

Int. J. Mol. Sci. 2024, 25(24), 13276; https://doi.org/10.3390/ijms252413276 - 11 Dec 2024

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Abstract

Diabetic sensorimotor neuropathy (DSPN) is strongly associated with the extent of cellular oxidative stress and endothelial dysfunction in type 2 diabetes (T2DM). Alpha-lipoic acid (ALA) attenuates the progression of DSPN through its antioxidant and vasculoprotective effects. Kallistatin has antioxidant and anti-inflammatory properties. We aimed to evaluate changes in kallistatin levels and markers of endothelial dysfunction in patients with T2DM and DSPN following six months of treatment with 600 mg/day of ALA. A total of 54 patients with T2DM and DSPN and 24 control patients with T2DM but without neuropathy participated in this study. The serum concentrations of kallistatin, ICAM-1, VCAM-1, oxLDL, VEGF, ADMA, and TNF-alpha were measured by an ELISA. Peripheral sensory neuropathy was assessed with neuropathy symptom questionnaires and determination of the current perception threshold. After ALA treatment, the level of kallistatin significantly decreased, as well as the levels of TNF-alpha and ADMA. Changes in kallistatin levels were positively correlated with changes in oxLDL. The improvement in DSPN symptoms following ALA treatment showed a positive correlation with changes in kallistatin, VEGF, oxLDL, and ADMA levels. Based on our results, kallistatin could represent a potential new biomarker for assessing therapeutic response during ALA treatment in patients with DSPN. Full article

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

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17 pages, 1798 KiB

Open AccessArticle

Weight Changes Are Linked to Adipose Tissue Genes in Overweight Women with Polycystic Ovary Syndrome

by Anton Hellberg, Daniel Salamon, Dorina Ujvari, Mikael Rydén and Angelica Lindén Hirschberg

Int. J. Mol. Sci. 2024, 25(21), 11566; https://doi.org/10.3390/ijms252111566 - 28 Oct 2024

Cited by 1 | Viewed by 1465

Abstract

Women with polycystic ovary syndrome (PCOS) have varying difficulties in achieving weight loss by lifestyle intervention, which may depend on adipose tissue metabolism. The objective was to study baseline subcutaneous adipose tissue gene expression as a prediction of weight loss by lifestyle intervention in obese/overweight women with PCOS. This is a secondary analysis of a randomized controlled trial where women with PCOS, aged 18–40 and body mass index (BMI) ≥ 27 were initially randomized to either a 4-month behavioral modification program or minimal intervention according to standard care. Baseline subcutaneous adipose tissue gene expression was related to weight change after the lifestyle intervention. A total of 55 obese/overweight women provided subcutaneous adipose samples at study entry. Weight loss was significant after behavioral modification (−2.2%, p = 0.0014), while there was no significant weight loss in the control group (−1.1%, p = 0.12). In microarray analysis of adipose samples, expression of 40 genes differed significantly between subgroups of those with the greatest weight loss or weight gain. 10 genes were involved in metabolic pathways including glutathione metabolism, gluconeogenesis, and pyruvate metabolism. Results were confirmed by real-time polymerase chain reaction (RT-PCR) in all 55 subjects. Expressions of GSTM5, ANLN, and H3C2 correlated with weight change (R = −0.41, p = 0.002; R = −0.31, p = 0.023 and R = −0.32, p = 0.016, respectively). GSTM5, involved in glutathione metabolism, was the strongest predictor of weight loss, and together with baseline waist-hip ratio (WHR) explained 31% of the variation in body weight change. This study shows that baseline subcutaneous adipose tissue genes play a role for body weight outcome in response to lifestyle intervention in overweight/obese women with PCOS. Full article

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

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14 pages, 1113 KiB

Open AccessArticle

The 5:2 Diet Affects Markers of Insulin Secretion and Sensitivity in Subjects with and without Type 2 Diabetes—A Non-Randomized Controlled Trial

by Neda Rajamand Ekberg, Anton Hellberg, Michaela Linn Sundqvist, Angelica Lindén Hirschberg, Sergiu-Bogdan Catrina and Kerstin Brismar

Int. J. Mol. Sci. 2024, 25(17), 9731; https://doi.org/10.3390/ijms25179731 - 8 Sep 2024

Cited by 3 | Viewed by 2944

Abstract

This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D. Full article

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

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13 pages, 5339 KiB

Open AccessArticle

Cilostazol Ameliorates Motor Dysfunction and Schwann Cell Impairment in Streptozotocin-Induced Diabetic Rats

by Lin-Li Chang, Yu-Ming Wu, Hung-Chen Wang, Kuang-Yi Tseng, Yi-Hsuan Wang, Yen-Mou Lu and Kuang-I Cheng

Int. J. Mol. Sci. 2024, 25(14), 7847; https://doi.org/10.3390/ijms25147847 - 18 Jul 2024

Cited by 2 | Viewed by 1453

Abstract

This study investigated the effects of cilostazol on motor dysfunction, spinal motor neuron abnormalities, and schwannopathy in rats with diabetes. Diabetes mellitus (DM) was induced in rats via femoral intravenous streptozotocin (STZ) injection (60 mg/kg). After successful DM induction, cilostazol was administered on day 15 via oral gavage (100 mg/kg/day) for 6 weeks until sacrifice. Behavioral assays, including motor function, were performed weekly. The sciatic nerve, L5 spinal cord, and spinal ventral root were collected to evaluate the expression of the glial fibrillary acidic protein (GFAP), myelin protein zero (P0), and choline acetyltransferase (ChAT) by immunofluorescence and Western blotting. DM rats displayed decreased running speeds, running distances, and toe spread but increased foot pressure. In addition, loss of non-myelinating Schwann cells and myelin sheaths was observed in the sciatic nerve and L5 spinal ventral root. Reduced numbers of motor neurons were also found in the L5 spinal ventral horn. Cilostazol administration significantly potentiated running speed and distance; increased hind paw toe spread; and decreased foot pressure. In the sciatic nerve and L5 spinal ventral root, cilostazol treatment significantly improved non-myelinated Schwann cells and increased myelin mass. ChAT expression in motor neurons in the spinal ventral horn was improved, but not significantly. Cilostazol administration may protect sensorimotor function in diabetic rats. Full article

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

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17 pages, 374 KiB

Open AccessReview

Rodent Models of Diabetic Neuropathy, Role of Calcium Homeostasis in Pain and KB-R7943 as a Potential Therapeutic

by Natasha Ivanova, Milen Hristov and Pavlina Gateva

Int. J. Mol. Sci. 2025, 26(5), 2094; https://doi.org/10.3390/ijms26052094 - 27 Feb 2025

Viewed by 565

Abstract

Diabetic neuropathy (DN) is characterized by nerve damage as a consequence of diabetes mellitus. Diabetes causes high blood glucose and triglyceride levels, which destroy the nerve blood vessels over time and trigger DN. Peripheral neuropathy is the most common type of DN, which encompasses a broad range of symptoms. One fourth of patients with diabetes suffer from neuropathic pain, which decreases their quality of life and puts them at high risk for emotional disturbances and depression. Finding an adequate therapy is an essential element in the cure of painful DN (PDN). Since the pathophysiology of this disease still needs to be elucidated, this has led to the development of various in vivo diabetic models. Animal models of DN not only provide insights into this disease but also are significant drivers for treatment assessment and improvement. In this review, we present the major features of the most commonly used chemically and diet-induced models of PDN in rodents and their progress to date, which are utilized for a better understanding of the disease mechanism for finding novel therapeutics. Considering the role of Ca²⁺ homeostasis in pain, we also review our recent research data on the Na⁺/Ca²⁺ exchanger blocker KB-R7943, which is a potential neuropathic pain reliever in a rodent model of DN. Full article

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

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16 pages, 748 KiB

Open AccessReview

Genetic Variants Influence the Development of Diabetic Neuropathy

by Noémi Hajdú, Ramóna Rácz, Dóra Zsuzsanna Tordai, Magdolna Békeffy, Orsolya Erzsébet Vági, Ildikó Istenes, Anna Erzsébet Körei, Peter Kempler and Zsuzsanna Putz

Int. J. Mol. Sci. 2024, 25(12), 6429; https://doi.org/10.3390/ijms25126429 - 11 Jun 2024

Cited by 2 | Viewed by 1886

Abstract

The exact mechanism by which diabetic neuropathy develops is still not fully known, despite our advances in medical knowledge. Progressing neuropathy may occur with a persistently favorable metabolic status in some patients with diabetes mellitus, while, in others, though seldom, a persistently unfavorable metabolic status is not associated with significant neuropathy. This might be significantly due to genetic differences. While recent years have brought compelling progress in the understanding of the pathogenetic background—in particular, accelerated progress is being made in understanding molecular biological mechanisms—some aspects are still not fully understood. A comparatively small amount of information is accessible on this matter; therefore, by summarizing the available data, in this review, we aim to provide a clearer picture of the current state of knowledge, identify gaps in the previous studies, and possibly suggest directions for future studies. This could help in developing more personalized approaches to the prevention and treatment of diabetic neuropathy, while also taking into account individual genetic profiles. Full article

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

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