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Diabetes and Complications of Diabetes: Pathophysiology, Mechanisms, and Therapies

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 5893

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Special Issue Editors

Prof. Dr. Daniel Petroviĉ

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Guest Editor

Institute of Histology and Embryology, Faculty of Medicine, University Ljubljana, Ljubljana, Korytkova 2, SI-1000 Ljubljana, Slovenia
Interests: Cardiology, Genetics, Gene polymorphisms, Diabetes, Microvascular and Macrovascular Complications

Dr. Draženka Pongrac Barlovič

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Guest Editor

Medical Faculty Ljubljana, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia
Interests: cardiology; genetics; gene polymorphisms; diabetes

Special Issue Information

Dear Colleagues,

Diabetes mellitus is a group of chronic diseases characterized by elevated blood glucose levels due to different causes with abnormal β-cell biology playing a pivotal role. In the last decades, the population affected by diabetes mellitus has been increasing in both developed and developing countries.

Diabetes increases the risk of premature mortality and morbidity as a result of multisystem complications during the life-long disease course. These include atherosclerotic cardiovascular diseases, renal failure, visual loss, foot ulcers and amputation, all of which are highly preventable and treatable.

Using both candidate gene and GWAS approaches, hundreds of genes and genetic loci associated with type 1 diabetes, type 2 diabetes, gestational diabetes mellitus and diabetic complications have been discovered. Many of these loci are implicated in islet development and β-cell biology.

Despite significant progress in the understanding of diabetes and its complications (pathogenesis, risk factors, new treatment modalities including β-cell transplantation), additional efforts are needed in this field.

Prof. Dr. Daniel Petroviĉ
Dr. Draženka Pongrac Barlovič
Guest Editors

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Keywords

diabetes mellitus
complications of diabetes
pathophysiology
mechanisms
genetics
epigenetics
therapies

Published Papers (7 papers)

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Research

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15 pages, 4260 KiB

Open AccessArticle

Glucose Promotes EMMPRIN/CD147 and the Secretion of Pro-Angiogenic Factors in a Co-Culture System of Endothelial Cells and Monocytes

by Fransis Ghandour, Sameer Kassem, Elina Simanovich and Michal A. Rahat

Biomedicines 2024, 12(4), 706; https://doi.org/10.3390/biomedicines12040706 - 22 Mar 2024

Viewed by 626

Abstract

Vascular complications in Type 2 diabetes mellitus (T2DM) patients increase morbidity and mortality. In T2DM, angiogenesis is impaired and can be enhanced or reduced in different tissues (“angiogenic paradox”). The present study aimed to delineate differences between macrovascular and microvascular endothelial cells that might explain this paradox. In a monoculture system of human macrovascular (EaHy926) or microvascular (HMEC-1) endothelial cell lines and a monocytic cell line (U937), high glucose concentrations (25 mmole/L) increased the secretion of the pro-angiogenic factors CD147/EMMPRIN, VEGF, and MMP-9 from both endothelial cells, but not from monocytes. Co-cultures of EaHy926/HMEC-1 with U937 enhanced EMMPRIN and MMP-9 secretion, even in low glucose concentrations (5.5 mmole/L), while in high glucose HMEC-1 co-cultures enhanced all three factors. EMMPRIN mediated these effects, as the addition of anti-EMMPRIN antibody decreased VEGF and MMP-9 secretion, and inhibited the angiogenic potential assessed through the wound assay. Thus, the minor differences between the macrovascular and microvascular endothelial cells cannot explain the angiogenic paradox. Metformin, a widely used drug for the treatment of T2DM, inhibited EMMPRIN, VEGF, and MMP-9 secretion in high glucose concentration, and the AMPK inhibitor dorsomorphin enhanced it. Thus, AMPK regulates EMMPRIN, a key factor in diabetic angiogenesis, suggesting that targeting EMMPRIN may help in the treatment of diabetic vascular complications. Full article

(This article belongs to the Special Issue Diabetes and Complications of Diabetes: Pathophysiology, Mechanisms, and Therapies)

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19 pages, 8052 KiB

Open AccessArticle

Protective Effect of Topiramate against Diabetic Retinopathy and Computational Approach Recognizing the Role of NLRP3/IL-1β/TNF-α Signaling

by Hala M. F. Mohammad, Mohamed Ahmed Eladl, Asmaa K. K. Abdelmaogood, Rabie E. Elshaer, Walaa Ghanam, Abdelhakeem Elaskary, Mohamed A. K. Saleh, Amira H. Eltrawy, Sahar K. Ali, Suzan M. M. Moursi, Shymaa E. Bilasy, Sawsan A. Zaitone, Wafa Ali Alzlaiq and Hayam Atteya

Biomedicines 2023, 11(12), 3202; https://doi.org/10.3390/biomedicines11123202 - 01 Dec 2023

Cited by 2 | Viewed by 965

Abstract

The possible impact of topiramate against diabetic retinopathy (DREN) and its molecular mechanisms in relation to the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome has not been studied before. Thus, in the present study, we aimed to utilize a computational approach to investigate the possible protective effect of topiramate on experimental DREN and explore its impact on NLRP3/interlukin-1β signaling and brain-derived neurotrophic factor (BDNF) expression. Male albino mice were distributed to four experimental groups and assigned the following categorizations: (i) saline, (ii) diabetic, (iii) diabetic + topiramate 10 mg/kg and (iv) diabetic + topiramate 30 mg/kg. We observed shrinkage of total retinal thickness and elevation in retinal glutamate, malondialdehyde, NLRP3 and interlukin-1β but decreased glutathione (GSH) levels in the diabetic mice. Additionally, retinal ultra-structures in the diabetic group showed abnormalities and vacuolations in the pigmented epithelium, the photoreceptor segment, the outer nuclear layer, the inner nuclear layer and the ganglion cell layer (GCL). Mice treated with topiramate 10 or 30 mg/kg showed downregulation in retinal malondialdehyde, NLRP3 and interlukin-1β levels; improvements in the retinal pathologies; enhanced immunostaining for BDNF and improved ultra-structures in different retinal layers. Overall, the current results suggest topiramate as a neuroprotective agent for DREN, and future studies are warranted to further elucidate the mechanism of its protective action. Full article

(This article belongs to the Special Issue Diabetes and Complications of Diabetes: Pathophysiology, Mechanisms, and Therapies)

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10 pages, 260 KiB

Open AccessArticle

Neuropsychological Aspects of Children’s Somatic Disorders in Chronic Diseases: Diabetes and Short Stature in the Developmental Period

by Maia Stanisławska-Kubiak, Katarzyna Wiecheć, Katarzyna Anna Majewska, Grażyna Teusz, Ewa Mojs and Andrzej Kędzia

Biomedicines 2023, 11(11), 3089; https://doi.org/10.3390/biomedicines11113089 - 17 Nov 2023

Viewed by 615

Abstract

Intellectual functioning studies carried out amongst children indicate that chronic diseases like type 1 diabetes and growth hormone deficiency (GHD), may, but do not necessarily, result in intellectual loss. Cognitive functions may decline as a child becomes older, as a disease persists over time and/or due to non-compliance with treatment recommendations or high stress levels. This study aimed to assess the cognitive functioning of children and youths with T1D and GHD-related short stature compared to healthy children. Methods: The study was carried out on 88 children with type 1 diabetes, 38 children suffering from short stature caused by (GHD), as well as a control group comprising 40 healthy children. Weschler’s tests were applied to measure intellectual and cognitive functions. Results: The results suggest that for children suffering from type 1 diabetes and short stature, their chronic childhood diseases per se do not impair cognitive development. It was observed that the higher the age of chronically ill children and the longer the disease persists, the lower their scores in individual cognitive subtests. For healthy children, age is correlated with the acquisition of particular skills and higher scores in specific subtests. Conclusions: On the basis of qualitative analysis of the cognitive functions subject to the study and close clinical observation of chronically ill children, we have been able to conclude that chronic diseases may alter cognitive functioning. Full article

(This article belongs to the Special Issue Diabetes and Complications of Diabetes: Pathophysiology, Mechanisms, and Therapies)

12 pages, 2115 KiB

Open AccessArticle

Analysis of Methylglyoxal Concentration in a Group of Patients with Newly Diagnosed Prediabetes

by Edyta Sutkowska, Izabela Fecka, Dominik Marciniak, Katarzyna Bednarska, Magdalena Sutkowska and Katarzyna Hap

Biomedicines 2023, 11(11), 2968; https://doi.org/10.3390/biomedicines11112968 - 03 Nov 2023

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Abstract

Background: The abnormal serum concentration of methylglyoxal (MGO) has been presented as an indicator of chronic complications in diabetes (DM). Because such complications are also found in pre-DM, we decided to assess the concentration of this compound in individuals with pre-DM, without cardio-vascular diseases. Methods: Frozen samples from individuals newly diagnosed with pre-DM (N = 31) and healthy subjects (N = 11) were prepared and MGO concentration was determined using UHPLC-ESI-QqTOF-MS. Results: Statistical significance was established when the groups were compared for body weight, BMI, fasting glucose level, fatty liver and use of statins but not for the other descriptive parameters. The positive linear correlation showed that the higher HbA1c, the higher MGO concentration (p = 0.01). The values of MGO were within the normal range in both groups (mean value for pre-DM: 135.44 nM (±SD = 32.67) and for the control group: 143.25 nM (±SD = 17.93); p = 0.46 (±95% CI)), with no statistical significance between the groups. Conclusions: We did not confirm the elevated MGO levels in the group of patients with pre-DM. The available data suggests a possible effect of statin intake on MGO levels. This thesis requires confirmation on a larger number of patients with an assessment of MGO levels before and after the introduction of statins. Full article

(This article belongs to the Special Issue Diabetes and Complications of Diabetes: Pathophysiology, Mechanisms, and Therapies)

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10 pages, 603 KiB

Open AccessArticle

Clinical Outcomes of Diabetic Ketoacidosis in Type 2 Diabetes Patients with and without SGLT2 Inhibitor Treatment: A Retrospective Study

by Afif Nakhleh, Areen Othman, Amin Masri, Moshe Zloczower, Sagit Zolotov and Naim Shehadeh

Biomedicines 2023, 11(10), 2689; https://doi.org/10.3390/biomedicines11102689 - 01 Oct 2023

Cited by 1 | Viewed by 858

Abstract

Aim: This study aimed to compare the clinical course and outcomes of DKA in T2DM patients who received treatment with SGLT2 inhibitors versus those who did not. Methods: A retrospective analysis was conducted on T2DM patients who were admitted to the Rambam Health Care Campus with DKA between 7/2015 and 9/2020. Demographic, clinical, and laboratory data were obtained from electronic medical records. Outpatient mortality was monitored until 12/2022. Results: Of 71 T2DM patients admitted with DKA, 16 (22.5%) were on SGLT2 inhibitor treatment upon admission. SGLT2 inhibitor users had a higher BMI and were less likely to be treated with insulin. During hospitalization, the rates of acute kidney injury, concomitant infections, and inpatient mortality among SGLT2 inhibitor users were comparable to non-users. The median follow-up period was 35.1 months for the SGLT2 inhibitor users and 36.7 months for non-users. The long-term mortality from any cause was lower among the SGLT2 inhibitor users (12.5% vs. 52.7%, p = 0.004). In Cox regression analysis, SGLT2 inhibitor use was associated with a lower risk of long-term mortality from any cause (HR = 0.19, p = 0.04). Conclusion: T2DM patients with DKA who received SGLT2 inhibitors had lower long-term mortality from any cause compared to those who did not receive SGLT2 inhibitors. Full article

(This article belongs to the Special Issue Diabetes and Complications of Diabetes: Pathophysiology, Mechanisms, and Therapies)

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13 pages, 1383 KiB

Open AccessArticle

Impacts of the DPP-4 Inhibitor Saxagliptin and SGLT-2 Inhibitor Dapagliflozin on the Gonads of Diabetic Mice

by Ali A. Alshamrani, Mohammed A. Al-Hamamah, Norah A. Albekairi, Mohamed S. M. Attia, Sheikh F. Ahmad, Mohammed A. Assiri, Mushtaq A. Ansari, Ahmed Nadeem, Saleh A. Bakheet, Wael A. Alanazi and Sabry M. Attia

Biomedicines 2023, 11(10), 2674; https://doi.org/10.3390/biomedicines11102674 - 29 Sep 2023

Cited by 2 | Viewed by 785

Abstract

Diabetes mellitus is a metabolic disease that can cause systemic problems, including testicular dysfunction. Several diabetes medications have demonstrated potential adverse effects on the male reproductive system; however, the effects of saxagliptin and dapagliflozin have not been sufficiently examined. This investigation studied the impacts of saxagliptin and dapagliflozin treatments on the gonads in a male mouse model of diabetes. Testicular disturbances were assessed by sperm DNA damage, diakinesis-metaphase I chromosome examination, and spermiogram analysis. Our results showed more sperm DNA damage, more spermatocyte chromosome aberrations, lower sperm motility/count, and more sperm morphological anomalies in diabetic mice than in the control mice. Dapagliflozin significantly restored all examined measures to the control values in diabetic mice, unlike saxagliptin, which exacerbated the reduction in sperm count and motility. Both drugs significantly restored the gonadal redox imbalances in diabetic mice by decreasing reactive oxygen species accumulation and increasing glutathione levels. In conclusion, our study presents preliminary evidence for the safety and efficacy of dapagliflozin in alleviating testicular abnormalities induced by diabetes, making it a promising candidate drug for patients with diabetes in their reproductive age. As saxagliptin may have negative effects on fertility, its prescription should be avoided in young male diabetic patients. Full article

(This article belongs to the Special Issue Diabetes and Complications of Diabetes: Pathophysiology, Mechanisms, and Therapies)

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Review

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21 pages, 1529 KiB

Open AccessReview

Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem

by Ildar Minniakhmetov, Bulat Yalaev, Rita Khusainova, Ekaterina Bondarenko, Galina Melnichenko, Ivan Dedov and Natalia Mokrysheva

Biomedicines 2024, 12(2), 399; https://doi.org/10.3390/biomedicines12020399 - 08 Feb 2024

Viewed by 947

Abstract

Omics technologies accumulated an enormous amount of data that advanced knowledge about the molecular pathogenesis of type 1 diabetes mellitus and identified a number of fundamental problems focused on the transition to personalized diabetology in the future. Among them, the most significant are the following: (1) clinical and genetic heterogeneity of type 1 diabetes mellitus; (2) the prognostic significance of DNA markers beyond the HLA genes; (3) assessment of the contribution of a large number of DNA markers to the polygenic risk of disease progress; (4) the existence of ethnic population differences in the distribution of frequencies of risk alleles and genotypes; (5) the infancy of epigenetic research into type 1 diabetes mellitus. Disclosure of these issues is one of the priorities of fundamental diabetology and practical healthcare. The purpose of this review is the systemization of the results of modern molecular genetic, transcriptomic, and epigenetic investigations of type 1 diabetes mellitus in general, as well as its individual forms. The paper summarizes data on the role of risk HLA haplotypes and a number of other candidate genes and loci, identified through genome-wide association studies, in the development of this disease and in alterations in T cell signaling. In addition, this review assesses the contribution of differential DNA methylation and the role of microRNAs in the formation of the molecular pathogenesis of type 1 diabetes mellitus, as well as discusses the most currently central trends in the context of early diagnosis of type 1 diabetes mellitus. Full article

(This article belongs to the Special Issue Diabetes and Complications of Diabetes: Pathophysiology, Mechanisms, and Therapies)

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