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Diabetes and Its Complications: Cellular and Molecular Mechanism and New...
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Diabetes and Its Complications: Cellular and Molecular Mechanism and New Therapeutic Opportunities

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Metabolism".

Deadline for manuscript submissions: closed (28 July 2023) | Viewed by 13122

Special Issue Editor

Dr. Salvatore Piro

E-Mail Website
Guest Editor
Ospedale Garibaldi Nesima, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Catania, Via Palermo 636, Catania, Italy
Interests: diabetes mellitus; pancreatic islets; insulin; glucagon; incretin; GLP-1; apoptosis; hormonal secretion
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Type 2 diabetes (T2D) is a chronic metabolic complex disease that is considered a global pandemic since its prevalence and incidence have progressively increased in recent decades. T2D pathogenesis is characterized by several factors including enhanced pancreatic alpha-cell deregulation, beta-cell dysfunction or death and insulin resistance. These alterations lead to chronic hyperglycemia that induces the activation of several pathways that are associated with blood vessel damage affecting both the microvasculature and macrovasculature. The major macrovascular complications are related to coronary artery disease, stroke and peripheral artery disease. The knowledge of the cellular and molecular mechanisms of diabetes complications is still limited. Most of the known dysregulated pathways are strictly linked to the chronic hyperglycemic state and reactive oxygen species (ROS) imbalance. Hyperglycemia is also associated with atherosclerotic abnormalities leading to macrovascular complications. The modulation of these pathways could represent a treatment strategy for diabetes complications. This Special Issue aims to obtain further insights into the already known cellular and molecular mechanisms related to diabetes complications, with a particular focus on the identification of novel strategies for their modulation. Furthermore, this Special Issue aims to identify novel potential molecular pathways of vascular damage in diabetes that could provide novel therapeutic targets.

Dr. Salvatore Piro
Guest Editor

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Keywords

  • insulin
  • glucagon
  • diabetes mellitus
  • complications
  • gastro-intestinal hormones

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Published Papers (5 papers)

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Research

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13 pages, 2073 KiB  
Article
Methylglyoxal-Modified Albumin Effects on Endothelial Arginase Enzyme and Vascular Function
by Ebaa M. Alzayadneh, Alia Shatanawi, R. William Caldwell and Ruth B. Caldwell
Cells 2023, 12(5), 795; https://doi.org/10.3390/cells12050795 - 3 Mar 2023
Cited by 2 | Viewed by 1861
Abstract
Advanced glycation end products (AGEs) contribute significantly to vascular dysfunction (VD) in diabetes. Decreased nitric oxide (NO) is a hallmark in VD. In endothelial cells, NO is produced by endothelial NO synthase (eNOS) from L-arginine. Arginase competes with NOS for L-arginine to produce [...] Read more.
Advanced glycation end products (AGEs) contribute significantly to vascular dysfunction (VD) in diabetes. Decreased nitric oxide (NO) is a hallmark in VD. In endothelial cells, NO is produced by endothelial NO synthase (eNOS) from L-arginine. Arginase competes with NOS for L-arginine to produce urea and ornithine, limiting NO production. Arginase upregulation was reported in hyperglycemia; however, AGEs’ role in arginase regulation is unknown. Here, we investigated the effects of methylglyoxal-modified albumin (MGA) on arginase activity and protein expression in mouse aortic endothelial cells (MAEC) and on vascular function in mice aortas. Exposure of MAEC to MGA increased arginase activity, which was abrogated by MEK/ERK1/2 inhibitor, p38 MAPK inhibitor, and ABH (arginase inhibitor). Immunodetection of arginase revealed MGA-induced protein expression for arginase I. In aortic rings, MGA pretreatment impaired acetylcholine (ACh)-induced vasorelaxation, which was reversed by ABH. Intracellular NO detection by DAF-2DA revealed blunted ACh-induced NO production with MGA treatment that was reversed by ABH. In conclusion, AGEs increase arginase activity probably through the ERK1/2/p38 MAPK pathway due to increased arginase I expression. Furthermore, AGEs impair vascular function that can be reversed by arginase inhibition. Therefore, AGEs may be pivotal in arginase deleterious effects in diabetic VD, providing a novel therapeutic target. Full article
(This article belongs to the Special Issue Diabetes and Its Complications: Cellular and Molecular Mechanism and New Therapeutic Opportunities)
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14 pages, 1826 KiB  
Article
New Treatment for Type 2 Diabetes Mellitus Using a Novel Bipyrazole Compound
by Abdelrahim Alqudah, Esam Y. Qnais, Mohammed A. Wedyan, Sara Altaber, Rawan Abudalo, Omar Gammoh, Hakam Alkhateeb, Sajeda Bataineh, Rabaa Y. Athamneh, Muna Oqal, Kayed Abu-Safieh and Lana McClements
Cells 2023, 12(2), 267; https://doi.org/10.3390/cells12020267 - 9 Jan 2023
Cited by 4 | Viewed by 2958
Abstract
2′,3,3,5′-Tetramethyl-4′-nitro-2′H-1,3′-bipyrazole (TMNB) is a novel bipyrazole compound with unknown therapeutic potential in diabetes mellitus. This study aims to investigate the anti-diabetic effects of TMNB in a high-fat diet and streptozotocin-(HFD/STZ)-induced rat model of type 2 diabetes mellitus (T2D). Rats were fed HFD, followed [...] Read more.
2′,3,3,5′-Tetramethyl-4′-nitro-2′H-1,3′-bipyrazole (TMNB) is a novel bipyrazole compound with unknown therapeutic potential in diabetes mellitus. This study aims to investigate the anti-diabetic effects of TMNB in a high-fat diet and streptozotocin-(HFD/STZ)-induced rat model of type 2 diabetes mellitus (T2D). Rats were fed HFD, followed by a single low dose of STZ (40 mg/kg). HFD/STZ diabetic rats were treated orally with TMNB (10 mg/kg) or (200 mg/kg) metformin for 10 days before terminating the experiment and collecting plasma, soleus muscle, adipose tissue, and liver for further downstream analysis. TMNB reduced the elevated levels of serum glucose in diabetic rats compared to the vehicle control group (p < 0.001). TMNB abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control rats (p < 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in the diabetic rats treated with TMNB compared to the vehicle controls. The skeletal muscle and adipose tissue protein contents of GLUT4 and AMPK were upregulated following treatment with TMNB (p < 0.001, < 0.01, respectively). TMNB was able to upregulate GLUT2 and AMPK protein expression in liver (p < 0.001, < 0.001, respectively). LDL, triglyceride, and cholesterol were reduced in diabetic rats treated with TMNB compared to the vehicle controls (p < 0.001, 0.01, respectively). TMNB reduced MDA and IL-6 levels (p < 0.001), and increased GSH level (p < 0.05) in diabetic rats compared to the vehicle controls. Conclusion: TMNB ameliorates insulin resistance, oxidative stress, and inflammation in a T2D model. TMNB could represent a promising therapeutic agent to treat T2D. Full article
(This article belongs to the Special Issue Diabetes and Its Complications: Cellular and Molecular Mechanism and New Therapeutic Opportunities)
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13 pages, 672 KiB  
Article
Investigating the Association between Diabetic Neuropathy and Vitamin D in Emirati Patients with Type 2 Diabetes Mellitus
by Tahra Al Ali, Alizeh Ashfaq, Narjes Saheb Sharif-Askari, Salah Abusnana and Bashair M. Mussa
Cells 2023, 12(1), 198; https://doi.org/10.3390/cells12010198 - 3 Jan 2023
Cited by 3 | Viewed by 2936
Abstract
(1) Background: Vitamin D deficiency is a common public health problem in the United Arab Emirates (UAE) and globally, and interestingly, improvements in diabetic neuropathy after taking Vitamin D supplementation for a short time have been reported. Despite living in a country that [...] Read more.
(1) Background: Vitamin D deficiency is a common public health problem in the United Arab Emirates (UAE) and globally, and interestingly, improvements in diabetic neuropathy after taking Vitamin D supplementation for a short time have been reported. Despite living in a country that is sunny all year round, hypovitaminosis D, indicated by an obvious low serum vitamin D level, has been recurrently noted in the UAE, as well as in the surrounding Arabian Gulf countries. This problem is receiving much attention and attracting clinical and academic interest. Therefore, the main objective of the present study is to identify the association, if any, between vitamin D deficiency and the development of diabetic neuropathy in the UAE population with T2DM. (2) Methods: a total of 600 Emirati patients (male and female) with T2DM, aged between 20 and 80, were recruited from University Hospital Sharjah (UHS). The medical records of the patients were reviewed and analyzed. (3) Results: The results of the present study showed that among the 600 patients, 50% were affected with diabetic neuropathy. Vitamin D level in patients with neuropathy were estimated to be around 20 ng/mL (IQR 14–25), and vitamin D levels were significantly higher (33 ng/mL (IQR 20–42)) among patients without neuropathy, with p < 0.001. Another important finding was that patients without neuropathy had a better vitamin D status, with only 19% being deficient and 18% having insufficient vitamin D levels, compared to patients with neuropathy, where 39% were deficient (vitamin D < 20 ng/mL) and 44% had insufficient vitamin D levels (20–30 ng/mL). (4) Conclusion: The findings of the present study show that the prevalence of vitamin D deficiency (low serum 25-hydroxy vitamin D 25-OHD level) is significantly high in diabetic neuropathy in Emirati patients with T2DM. Full article
(This article belongs to the Special Issue Diabetes and Its Complications: Cellular and Molecular Mechanism and New Therapeutic Opportunities)
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Review

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11 pages, 613 KiB  
Review
An Overview of the Role of Furin in Type 2 Diabetes
by Sulaiman K. Marafie and Fahd Al-Mulla
Cells 2023, 12(19), 2407; https://doi.org/10.3390/cells12192407 - 5 Oct 2023
Cited by 2 | Viewed by 1794
Abstract
Post-translational modifications (PTMs) play important roles in regulating several human diseases, like cancer, neurodegenerative disorders, and metabolic disorders. Investigating PTMs’ contribution to protein functions is critical for modern biology and medicine. Proprotein convertases (PCs) are irreversible post-translational modifiers that have been extensively studied [...] Read more.
Post-translational modifications (PTMs) play important roles in regulating several human diseases, like cancer, neurodegenerative disorders, and metabolic disorders. Investigating PTMs’ contribution to protein functions is critical for modern biology and medicine. Proprotein convertases (PCs) are irreversible post-translational modifiers that have been extensively studied and are considered as key targets for novel therapeutics. They cleave proteins at specific sites causing conformational changes affecting their functions. Furin is considered as a PC model in regulating growth factors and is involved in regulating many pro-proteins. The mammalian target of the rapamycin (mTOR) signaling pathway is another key player in regulating cellular processes and its dysregulation is linked to several diseases including type 2 diabetes (T2D). The role of furin in the context of diabetes has been rarely explored and is currently lacking. Moreover, furin variants have altered activity that could have implications on overall health. In this review, we aim to highlight the role of furin in T2D in relation to mTOR signaling. We will also address furin genetic variants and their potential effect on T2D and β-cell functions. Understanding the role of furin in prediabetes and dissecting it from other confounding factors like obesity is crucial for future therapeutic interventions in metabolic disorders. Full article
(This article belongs to the Special Issue Diabetes and Its Complications: Cellular and Molecular Mechanism and New Therapeutic Opportunities)
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16 pages, 1184 KiB  
Review
Diabetes and Its Cardiovascular Complications: Potential Role of the Acetyltransferase p300
by Nadia Di Pietrantonio, Pamela Di Tomo, Domitilla Mandatori, Gloria Formoso and Assunta Pandolfi
Cells 2023, 12(3), 431; https://doi.org/10.3390/cells12030431 - 28 Jan 2023
Cited by 15 | Viewed by 2593
Abstract
Diabetes has been shown to accelerate vascular senescence, which is associated with chronic inflammation and oxidative stress, both implicated in the development of endothelial dysfunction. This condition represents the initial alteration linking diabetes to related cardiovascular (CV) complications. Recently, it has been hypothesised [...] Read more.
Diabetes has been shown to accelerate vascular senescence, which is associated with chronic inflammation and oxidative stress, both implicated in the development of endothelial dysfunction. This condition represents the initial alteration linking diabetes to related cardiovascular (CV) complications. Recently, it has been hypothesised that the acetyltransferase, p300, may contribute to establishing an early vascular senescent phenotype, playing a relevant role in diabetes-associated inflammation and oxidative stress, which drive endothelial dysfunction. Specifically, p300 can modulate vascular inflammation through epigenetic mechanisms and transcription factors acetylation. Indeed, it regulates the inflammatory pathway by interacting with nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (NF-κB p65) or by inducing its acetylation, suggesting a crucial role of p300 as a bridge between NF-κB p65 and the transcriptional machinery. Additionally, p300-mediated epigenetic modifications could be upstream of the activation of inflammatory cytokines, and they may induce oxidative stress by affecting the production of reactive oxygen species (ROS). Because several in vitro and in vivo studies shed light on the potential use of acetyltransferase inhibitors, a better understanding of the mechanisms underlying the role of p300 in diabetic vascular dysfunction could help in finding new strategies for the clinical management of CV diseases related to diabetes. Full article
(This article belongs to the Special Issue Diabetes and Its Complications: Cellular and Molecular Mechanism and New Therapeutic Opportunities)
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