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Cellular and Molecular Mechanisms in Diabetes Development and Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 10903

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Prof. Dr. Young-Hee Kang

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Guest Editor

Department of Food Science and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Republic of Korea
Interests: phytochemicals; diabetic nephropathy; diabetic retinopathy; diabetes; osteoporosis; pulmonary diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Min-Kyung Kang

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Guest Editor

Department of Food and Nutrition, Andong National University, Andong 36729, Republic of Korea
Interests: bioactive compounds; functional food; metabolic diseases; diabetes; diabetic complications

Special Issue Information

Dear Colleagues,

Diabetes is a chronic disease characterized by hyperglycemia, which occurs when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. The prevalence and incidence of diabetes continue to increase, with reports predicting that 783 million adults worldwide will be living with diabetes by 2045. Long-term exposure to hyperglycemia can cause serious damage to the body's systems, leading to an increased risk of various complications of diabetes. Diabetes is associated with a number of complications, which can be classified as macrovascular disease or microvascular disease. The major macrovascular complications include accelerated cardiovascular disease, resulting in myocardial infarction and cerebrovascular disease, which manifest as strokes. Microvascular complications include eye disease (retinopathy), kidney disease (nephropathy), and neural damage (neuropathy).

This Special Issue aims to comprehensively discuss the validated as well as putative mechanisms involved in the development of diabetes and its complications. Furthermore, this Special Issue entitled "Cellular and Molecular Mechanisms in Diabetes Development and Therapies" aims to provide new insights into the overall cellular and molecular mechanisms related to diabetes and the various diseases caused by diabetes. These insights could lead to the discovery of novel therapeutic targets.

Prof. Dr. Young-Hee Kang
Dr. Min-Kyung Kang
Guest Editors

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Keywords

diabetes
diabetic complication
cardiovascular disease
retinopathy
nephropathy
neuropathy

Published Papers (5 papers)

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Research

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24 pages, 6538 KiB

Open AccessArticle

Comparative Screening of the Liver Gene Expression Profiles from Type 1 and Type 2 Diabetes Rat Models

by Paloma Lucía Guerra-Ávila, Tereso J. Guzmán, Belinda Vargas-Guerrero, José Alfredo Domínguez-Rosales, Alejandra Beatriz Cervantes-Garduño, Adriana María Salazar-Montes, Laura Verónica Sánchez-Orozco and Carmen Magdalena Gurrola-Díaz

Int. J. Mol. Sci. 2024, 25(8), 4151; https://doi.org/10.3390/ijms25084151 - 9 Apr 2024

Viewed by 602

Abstract

Experimental animal models of diabetes can be useful for identifying novel targets related to disease, for understanding its physiopathology, and for evaluating emerging antidiabetic treatments. This study aimed to characterize two rat diabetes models: HFD + STZ, a high-fat diet (60% fat) combined with streptozotocin administration (STZ, 35 mg/kg BW), and a model with a single STZ dose (65 mg/kg BW) in comparison with healthy rats. HFD + STZ- induced animals demonstrated a stable hyperglycemia range (350–450 mg/dL), whereas in the STZ-induced rats, we found glucose concentration values with a greater dispersion, ranging from 270 to 510 mg/dL. Moreover, in the HFD + STZ group, the AUC value of the insulin tolerance test (ITT) was found to be remarkably augmented by 6.2-fold higher than in healthy animals (33,687.0 ± 1705.7 mg/dL/min vs. 5469.0 ± 267.6, respectively), indicating insulin resistance (IR). In contrast, a more moderate AUC value was observed in the STZ group (19,059.0 ± 3037.4 mg/dL/min) resulting in a value 2.5-fold higher than the average exhibited by the control group. After microarray experiments on liver tissue from all animals, we analyzed genes exhibiting a fold change value in gene expression <−2 or >2 (p-value <0.05). We found 27,686 differentially expressed genes (DEG), identified the top 10 DEGs and detected 849 coding genes that exhibited opposite expression patterns between both diabetes models (491 upregulated genes in the STZ model and 358 upregulated genes in HFD + STZ animals). Finally, we performed an enrichment analysis of the 849 selected genes. Whereas in the STZ model we found cellular pathways related to lipid biosynthesis and metabolism, in the HFD + STZ model we identified pathways related to immunometabolism. Some phenotypic differences observed in the models could be explained by transcriptomic results; however, further studies are needed to corroborate these findings. Our data confirm that the STZ and the HFD + STZ models are reliable experimental models for human T1D and T2D, respectively. These results also provide insight into alterations in the expression of specific liver genes and could be utilized in future studies focusing on diabetes complications associated with impaired liver function. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Diabetes Development and Therapies)

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11 pages, 495 KiB

Open AccessArticle

Association of Klotho with Coronary Artery Disease in Subjects with Type 2 Diabetes Mellitus and Preserved Kidney Function: A Case-Control Study

by Javier Donate-Correa, Ernesto Martín-Núñez, Carmen Mora-Fernández, Ainhoa González-Luis, Alberto Martín-Olivera and Juan F. Navarro-González

Int. J. Mol. Sci. 2023, 24(17), 13456; https://doi.org/10.3390/ijms241713456 - 30 Aug 2023

Cited by 1 | Viewed by 891

Abstract

Circulating Klotho levels are significantly reduced in subjects with type 2 diabetes mellitus (T2DM) and in kidney disease patients. In this work, the relationship between Klotho levels and the coronary artery disease (CAD) burden in subjects with T2DM and preserved kidney function was analyzed. For this, we performed a cross-sectional case-control study involving 133 subjects with T2DM and 200 age-, sex- and CAD-incidence-matched, non-diabetic patients undergoing non-emergency diagnostic coronary angiography. All of them were non-albuminuric and with normal glomerular filtration rates. The concentrations of serum Klotho, fibroblast growth factor 23, and inflammatory markers were also measured. As expected, the serum Klotho concentration was lower in the T2DM group (12.3% lower, p = 0.04). However, within the group of patients with T2DM, those subjects with CAD presented significantly higher Klotho levels than those without significant coronary stenosis (314.5 (6.15–562.81) vs. 458.97 (275.2–667.2) pg/mL; p = 0.02). Multiple regression analysis revealed that serum Klotho was positively related with stenosis values exclusively in subjects with T2DM (adjusted R2 = 0.153, p < 0.01). Moreover, logistic regression analysis showed that Klotho was positively associated with the presence of significant CAD in the group of T2DM patients (OR: 1.001; p = 0.041). Our data suggest that higher levels of circulating Klotho in subjects with T2DM and preserved kidney function are associated with the presence of significant CAD. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Diabetes Development and Therapies)

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12 pages, 7175 KiB

Open AccessArticle

Denosumab Attenuates Glucolipotoxicity-Induced β-Cell Dysfunction and Apoptosis by Attenuating RANK/RANKL Signals

by Sheng-Chieh Lin, Sing-Hua Tsou, Chien-Yin Kuo, Wei-Liang Chen, Kuan-Wen Wu, Chih-Li Lin and Chien-Ning Huang

Int. J. Mol. Sci. 2023, 24(12), 10289; https://doi.org/10.3390/ijms241210289 - 17 Jun 2023

Cited by 4 | Viewed by 1410

Abstract

Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the progression of T2D. Therefore, the prevention of β-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting β-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of β-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-κB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 × 10⁷ β-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect β-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in β-cells. This may be caused by blocking the RANK/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect β-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of β-cells. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Diabetes Development and Therapies)

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Review

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22 pages, 428 KiB

Open AccessReview

Diabetic Nephropathy: Significance of Determining Oxidative Stress and Opportunities for Antioxidant Therapies

by Marina Darenskaya, Sergey Kolesnikov, Natalya Semenova and Lyubov Kolesnikova

Int. J. Mol. Sci. 2023, 24(15), 12378; https://doi.org/10.3390/ijms241512378 - 3 Aug 2023

Cited by 6 | Viewed by 1762

Abstract

Diabetes mellitus (DM) belongs to the category of socially significant diseases with epidemic rates of increases in prevalence. Diabetic nephropathy (DN) is a specific kind of kidney damage that occurs in 40% of patients with DM and is considered a serious complication of DM. Most modern methods for treatments aimed at slowing down the progression of DN have side effects and do not produce unambiguous positive results in the long term. This fact has encouraged researchers to search for additional or alternative treatment methods. Hyperglycemia has a negative effect on renal structures due to a number of factors, including the activation of the polyol and hexosamine glucose metabolism pathways, the activation of the renin–angiotensin–aldosterone and sympathetic nervous systems, the accumulation of advanced glycation end products and increases in the insulin resistance and endothelial dysfunction of tissues. The above mechanisms cause the development of oxidative stress (OS) reactions and mitochondrial dysfunction, which in turn contribute to the development and progression of DN. Modern antioxidant therapies for DN involve various phytochemicals (food antioxidants, resveratrol, curcumin, alpha-lipoic acid preparations, etc.), which are widely used not only for the treatment of diabetes but also other systemic diseases. It has also been suggested that therapeutic approaches that target the source of reactive oxygen species in DN may have certain advantages in terms of nephroprotection from OS. This review describes the significance of studies on OS biomarkers in the pathogenesis of DN and analyzes various approaches to reducing the intensity of OS in the prevention and treatment of DN. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Diabetes Development and Therapies)

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26 pages, 8353 KiB

Open AccessReview

An Update on the Molecular and Cellular Basis of Pharmacotherapy in Type 2 Diabetes Mellitus

by Mohamed Omer Mahgoub, Ifrah Ismail Ali, Jennifer O. Adeghate, Kornélia Tekes, Huba Kalász and Ernest A. Adeghate

Int. J. Mol. Sci. 2023, 24(11), 9328; https://doi.org/10.3390/ijms24119328 - 26 May 2023

Cited by 7 | Viewed by 5641

Abstract

Diabetes mellitus (DM) is a chronic illness with an increasing global prevalence. More than 537 million cases of diabetes were reported worldwide in 2021, and the number is steadily increasing. The worldwide number of people suffering from DM is projected to reach 783 million in 2045. In 2021 alone, more than USD 966 billion was spent on the management of DM. Reduced physical activity due to urbanization is believed to be the major cause of the increase in the incidence of the disease, as it is associated with higher rates of obesity. Diabetes poses a risk for chronic complications such as nephropathy, angiopathy, neuropathy and retinopathy. Hence, the successful management of blood glucose is the cornerstone of DM therapy. The effective management of the hyperglycemia associated with type 2 diabetes includes physical exercise, diet and therapeutic interventions (insulin, biguanides, second generation sulfonylureas, glucagon-like peptide 1 agonists, dipeptidyl-peptidase 4 inhibitors, thiazolidinediones, amylin mimetics, meglitinides, α-glucosidase inhibitors, sodium-glucose cotransporter-2 inhibitors and bile acid sequestrants). The optimal and timely treatment of DM improves the quality of life and reduces the severe burden of the disease for patients. Genetic testing, examining the roles of different genes involved in the pathogenesis of DM, may also help to achieve optimal DM management in the future by reducing the incidence of DM and by enhancing the use of individualized treatment regimens. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Diabetes Development and Therapies)

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