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Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches

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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: 20 December 2024 | Viewed by 7675

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Dr. Andrea Paola Rojas Gil

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Department of Nursing, Faculty of Health Sciences, University of Peloponnese, 22100 Tripoli, Greece
Interests: diabetes; nutrition; oncology; metabolisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia due insulin insufficiency or impaired insulin action. Diabetes could affects the quality of life and survival of patients. Recent data from the International Diabetes Federation showed that by 2045 it is expected to reach 783 million patients. Diabetes carries an increased risk for cardiovascular diseases including kidney failure. Different elements of the environment have been posited to influence the appearance of diabetes mellitus. Sleep and diet are key factors in regulating glucose metabolism, which is also significantly affected by physical activity. Air pollution has been shown to change endothelial function, and systemic inflammation, and trigger insulin resistance. The genetic background determines the predisposition to develop diabetes while the autoimmune related to diabetes seems to be also determined by environmental triggers, such as endocrine disrupting chemicals (EDCs). This Special Issue of the International Journal of Molecular Sciences focuses on the molecular and metabolic mechanism related to the appearance and complications of diabetes, emphasizing on environmental factors, and possible applications related to interventions and therapy.

Dr. Andrea Paola Rojas Gil
Guest Editor

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Keywords

diabetes
diabetes complications
enviromental factors
endocrine disruptors
nutrition
sleep
therapy
molecular mechanisms

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Published Papers (7 papers)

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Research

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16 pages, 3522 KiB

Open AccessArticle

Repurposing Niclosamide to Modulate Renal RNA-Binding Protein HuR for the Treatment of Diabetic Nephropathy in db/db Mice

by Lili Zhuang, Wenjin Liu, Xiao-Qing Tsai, Connor Outtrim, Anna Tang, Zhou Wang and Yufeng Huang

Int. J. Mol. Sci. 2024, 25(17), 9651; https://doi.org/10.3390/ijms25179651 - 6 Sep 2024

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Abstract

Hu antigen R (HuR) plays a key role in regulating genes critical to the pathogenesis of diabetic nephropathy (DN). This study investigates the therapeutic potential of niclosamide (NCS) as an HuR inhibitor in DN. Uninephrectomized mice were assigned to four groups: normal control; untreated db/db mice terminated at 14 and 22 weeks, respectively; and db/db mice treated with NCS (20 mg/kg daily via i.p.) from weeks 18 to 22. Increased HuR expression was observed in diabetic kidneys from db/db mice, which was mitigated by NCS treatment. Untreated db/db mice exhibited obesity, progressive hyperglycemia, albuminuria, kidney hypertrophy and glomerular mesangial matrix expansion, increased renal production of fibronectin and a-smooth muscle actin, and decreased glomerular WT-1⁺-podocytes and nephrin expression. NCS treatment did not affect mouse body weight, but reduced blood glucose and HbA1c levels and halted the DN progression observed in untreated db/db mice. Renal production of inflammatory and oxidative stress markers (NF-κBp65, TNF-a, MCP-1) and urine MDA levels increased during disease progression in db/db mice but were halted by NCS treatment. Additionally, the Wnt1-signaling-pathway downstream factor, Wisp1, was identified as a key downstream mediator of HuR-dependent action and found to be markedly increased in db/db mouse kidneys, which was normalized by NCS treatment. These findings suggest that inhibition of HuR with NCS is therapeutic for DN by improving hyperglycemia, renal inflammation, and oxidative stress. The reduction in renal Wisp1 expression also contributes to its renoprotective effects. This study supports the potential of repurposing HuR inhibitors as a novel therapy for DN. Full article

(This article belongs to the Special Issue Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches)

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13 pages, 667 KiB

Open AccessArticle

A One-Month Advanced Glycation End Products—Restricted Diet Improves CML, RAGE, Metabolic and Inflammatory Profile in Patients with End-Stage Renal Disease Undergoing Haemodialysis

by Adamantia Aroni, Paraskevi Detopoulou, Demetrios Presvelos, Eirini Kostopoulou, Anastasios Ioannidis, George I. Panoutsopoulos, Sofia Zyga, Georgios Kosmidis, Bessie E. Spiliotis and Andrea Paola Rojas Gil

Int. J. Mol. Sci. 2024, 25(16), 8893; https://doi.org/10.3390/ijms25168893 - 15 Aug 2024

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Abstract

Exogenous and endogenous advanced glycation end products (AGEs) contribute to the pathogenesis and progression of renal disease. This is a one-month controlled dietary counseling trial that restricts nutritional AGEs in patients with end-stage renal disease (ESRD) undergoing haemodialysis (n = 22 participants in the intervention and n = 20 participants in the control group). Haematological, biochemical markers, the soluble form of the receptor for AGEs (sRAGE), and carboxymethyl lysine (CML) were measured at baseline and at follow-up. Mononuclear cells were isolated and the protein expression of RAGE and the inflammatory marker COX-2 was measured using Western immunoblotting. The intervention group presented a lower increase in CML compared to the control group (12.39% median change in the intervention vs. 69.34% in the control group, p = 0.013), while RAGE (% mean change −56.54 in the intervention vs. 46.51 in the control group, p < 0.001) and COX-2 (% mean change −37.76 in the intervention vs. 0.27 in the control group, p < 0.001) were reduced compared to the control group. sRAGE was reduced in both groups. In addition, HbA1c (at two months), total cholesterol, and triglycerides were reduced in the intervention versus the control group. The adoption of healthy cooking methods deserves further research as a possible way of modulating inflammatory markers in patients with CKD. Full article

(This article belongs to the Special Issue Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches)

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16 pages, 4917 KiB

Open AccessArticle

Eucalyptol Ameliorates Retinal Microvascular Defects through Modulating ER Stress and Angiopoietin–Tie Signaling in Diabetic Eyes

by Dong Yeon Kim, Sin-Hye Park, Zaee Yoon, Jimin Kim, Min-Kyung Kang and Young-Hee Kang

Int. J. Mol. Sci. 2024, 25(14), 7826; https://doi.org/10.3390/ijms25147826 - 17 Jul 2024

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Abstract

Loss of the inner blood–retinal barrier (BRB) integrity is a main feature of ocular diseases such as diabetic macular edema. However, there is a lack of clarity on how inner BRB function is modulated within the diabetic retina. The current study examined whether eucalyptol inhibited inner BRB destruction and aberrant retinal angiogenesis in 33 mM glucose-exposed human retinal microvascular endothelial (RVE) cells and db/db mice. This study further examined the molecular mechanisms underlying endothelial dysfunction including retinal endoplasmic reticulum (ER) stress and angiopoietin (Ang)/Tie axis in conjunction with vascular endothelial growth factor (VEGF). Eucalyptol is a naturally occurring monoterpenoid and an achiral aromatic component of many plants including eucalyptus leaves. Nontoxic eucalyptol reduced the production of amyloid-β (Aβ) protein in glucose-loaded RVE cells and in diabetic mice. This natural compound blocked apoptosis of Aβ-exposed RVE cells in diabetic mouse eyes by targeting ER stress via the inhibition of PERK-eIF2α-ATF4-CHOP signaling. Eucalyptol promoted activation of the Ang-1/Tie-2 pathway and dual inhibition of Ang-2/VEGF in Aβ-exposed RVE cells and in diabetic eyes. Supply of eucalyptol reversed the induction of junction proteins in glucose/Aβ-exposed RVE cells within the retina and reduced permeability. In addition, oral administration of eucalyptol reduced vascular leaks in diabetic retinal vessels. Taken together, these findings clearly show that eucalyptol inhibits glucose-induced Aβ-mediated ER stress and manipulates Ang signaling in diabetic retinal vessels, which ultimately blocks abnormal angiogenesis and loss of inner BRB integrity. Therefore, eucalyptol provides new treatment strategies for diabetes-associated RVE defects through modulating diverse therapeutic targets including ER stress, Ang-1/Tie-2 signaling, and Ang-2/VEGF. Full article

(This article belongs to the Special Issue Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches)

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20 pages, 20927 KiB

Open AccessArticle

Serotonin and Interleukin 10 Can Influence the Blood and Urine Viscosity in Gestational Diabetes Mellitus and Pregnancy-Specific Urinary Incontinence

by Danielle Cristina Honório França, Adenilda Cristina Honorio-França, Kênia Maria Rezende Silva, Fernanda Cristina Bérgamo Alves, Gabriela Bueno, Sarah Maria Barneze Costa, Aron Carlos de Melo Cotrim, Angélica Mércia Pascon Barbosa, Eduardo Luzía França, Marilza Vieira Cunha Rudge and The Diamater Study Group

Int. J. Mol. Sci. 2023, 24(24), 17125; https://doi.org/10.3390/ijms242417125 - 5 Dec 2023

Cited by 1 | Viewed by 1338

Abstract

Serotonin and interleukin 10 (IL-10) may play a role in gestational diabetes mellitus. Hyperglycemic environment, the detrusor musculature of the bladder and pelvic floor muscles may become damaged, leading to urination problems and urine viscosity in pregnant women with gestational diabetes mellitus and pregnancy-specific urinary incontinence. Urine and blood samples were collected from pregnant women between 24 and 28 weeks of gestation. The serotonin concentration and cytokine IL-10 levels were evaluated in plasma and urine. In the total blood and urine, the viscosity was evaluated in the presence and absence of exogenous serotonin and IL-10. The plasma serotonin levels decreased, while the urine serotonin levels increased in the normoglycemic incontinent (NG-I), hyperglycemic continent (GDM-C), and hyperglycemic incontinent (GDM-I) groups. The IL-10 in the plasma decreased in the GDM-I group and was higher in the urine in the NG-I and GDM-I groups. The blood viscosity was higher, independently of urinary incontinence, in the GDM groups. The serotonin increased the blood viscosity from women with GDM-C and urine in the NG-I, GDM-C, and GDM-I groups. Blood and urine in the presence of IL-10 showed a similar viscosity in all groups studied. Also, no difference was observed in the viscosity in either the blood or urine when in the presence of serotonin and IL-10. These findings suggest that serotonin and IL-10 have the potential to reduce blood viscosity in pregnant women with gestational diabetes and specific urinary incontinence, maintaining values similar to those in normoglycemic women’s blood. Full article

(This article belongs to the Special Issue Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches)

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17 pages, 1965 KiB

Open AccessArticle

The Response of Antioxidant Enzymes and Antiapoptotic Markers to an Oral Glucose Tolerance Test (OGTT) in Children and Adolescents with Excess Body Weight

by Maria Efthymia Katsa, Eirini Kostopoulou, Tzortzis Nomikos, Anastasios Ioannidis, Vasileios Sarris, Spyridon Papadogiannis, Bessie E. Spiliotis and Andrea Paola Rojas Gil

Int. J. Mol. Sci. 2023, 24(22), 16517; https://doi.org/10.3390/ijms242216517 - 20 Nov 2023

Viewed by 1098

Abstract

Oxidative stress and apoptosis are involved in the pathogenesis of obesity-related diseases. This observational study investigates the antioxidant and apoptotic markers response to an oral glucose tolerance test (OGTT) in a population of overweight children and adolescents, with normal (NGT) or impaired glucose tolerance (IGT). Glucose, insulin, and C-peptide concentrations, as well as oxidative stress (SOD, GPx3) and apoptotic markers (Apo1fas, cck18), were determined at T = 0, 30, 60, 90, 120, and 180 min after glucose intake during OGTT. The lipid profile, thyroid function, insulin-like growth factor1, leptin, ghrelin, and adiponectin were also measured at baseline. The 45 participants, with a mean age of 12.15 (±2.3) years old, were divided into two subcategories: those with NGΤ (n = 31) and those with IGT (n = 14). The area under the curve (AUC) of glucose, insulin, and C-peptide was greater in children with IGT; however, only glucose differences were statistically significant. SOD and GPx3 levels were higher at all time points in the IGT children. Apo1fas and cck18 levels were higher in the NGT children at most time points, whereas Adiponectin was lower in the IGT group. Glucose increased during an OGTT accompanied by a simultaneous increase in antioxidant factors, which may reflect a compensatory mechanism against the impending increase in oxidative stress in children with IGT. Full article

(This article belongs to the Special Issue Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches)

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10 pages, 1217 KiB

Open AccessArticle

Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells

by Mirabela Hali, Nelson Pinto, Noah Gleason and Anjaneyulu Kowluru

Int. J. Mol. Sci. 2023, 24(21), 15994; https://doi.org/10.3390/ijms242115994 - 6 Nov 2023

Viewed by 1865

Abstract

CARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9 in islet β-cell dysregulation under duress of gluco (HG)- and glucolipotoxic (GLT) stress. CARD9 expression was also increased in β-cells following exposure to HG and GLT stress. The current study is aimed at understanding the putative roles of histone deacetylation in HG- and GLT-induced expression of CARD9. Using two structurally distinct inhibitors of histone deacetylases (HDACs), namely trichostatin (TSA) and suberoylanilide hydroxamic acid (SAHA), we provide the first evidence to suggest that the increased expression of CARD9 seen under duress of HG and GLT stress is under the regulatory control of histone deacetylation. Interestingly, the expression of protein kinase Cδ (PKCδ), a known upstream regulator of CARD9 activation, is also increased under conditions of metabolic stress. However, it is resistant to TSA and SAHA, suggesting that it is not regulated via histone deacetylation. Based on these data, we propose that targeting the appropriate HDACs, which mediate the expression (and function) of CARD9, might be the next step to further enhance our current understanding of the roles of CARD9 in islet dysfunction under metabolic stress and diabetes. Full article

(This article belongs to the Special Issue Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches)

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11 pages, 600 KiB

Open AccessReview

A Brief Overview of Cholinergic and Phosphodiesterase-5 Inhibitors in Diabetic Bladder Dysfunction

by Georgios Kallinikas, Georgios Haronis, Eirini Kallinika, Diomidis Kozyrakis, Evangelos Rodinos, Athanasios Filios, Panagiotis Filios, Despoina Mityliniou, Konstantinos Safioleas, Anastasios Zarkadas, Dimitrios Bozios, Athanasios Karmogiannis, Vasileios Konstantinopoulos, Anna Maria Konomi, Amin M. Ektesabi and James N. Tsoporis

Int. J. Mol. Sci. 2024, 25(19), 10704; https://doi.org/10.3390/ijms251910704 - 4 Oct 2024

Viewed by 666

Abstract

Diabetic bladder dysfunction (DBD) comprises a wide spectrum of lower urinary tract symptoms that impact diabetic patients’ lives, including urinary frequency, urgency, incontinence, and incomplete bladder emptying. To relieve symptoms, anticholinergics have been widely prescribed and are considered an effective treatment. There is increasing evidence that diabetic patients may benefit from the use of phosphodiesterase 5 (PDE5) inhibitors. This narrative review aims to provide a brief overview of the pathophysiology of DBD along with a focus on cholinergic and phosphodiesterase inhibitors as therapies that benefit DBD. An examination of the literature suggests compelling avenues of research and underscores critical gaps in understanding the mechanisms underlying DBD. New tools and models, especially rodent models, are required to further elucidate the mechanisms of action of current therapies in the treatment of DBS. Full article

(This article belongs to the Special Issue Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches)

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