scholarly journals MicroRNAs Regulate the Wnt/Ca2+ Signaling Pathway to Promote the Secretion of Insulin in Pancreatic Nestin-Positive Progenitor Cells

2014 ◽  
Author(s):  
Chunyu Bai ◽  
Xiangchen Li ◽  
Yuhua Gao ◽  
Taofeng Lu ◽  
Kunfu Wang ◽  
...  

MicroRNAs (miRNAs) are small noncoding RNAs that bind to the 3?-UTR of mRNAs and function mainly in post-transcriptional regulation. MiRNAs have been implicated to play roles in organ development, including that of the pancreas. Many miRNAs, such as miR-375, miR-124, miR-7, miR-21 and miR-221, have been shown to regulate insulin production as well as insulin secretion. However, it is not known whether miRNAs can regulate insulin secretion via the control of intracellular Ca2+ in pancreatic beta cells. In this research, expression profiles of miRNAs and mRNAs were investigated using RNA-sequencing and microarray analysis in chicken pancreatic nestin-positive progenitor cells and differentiated pancreatic beta cells. A number of miRNAs were up-regulated after differentiation of progenitors into beta cells, which regulate cell signaling pathways to control cell function. miR-223 and miR146a were shown to promote insulin secretion from pancreatic beta cells by regulating the concentration of intracellular Ca2+ via the down-regulation of their target genes.

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0241349
Author(s):  
Sajid Ali Rajput ◽  
Munazza Raza Mirza ◽  
M. Iqbal Choudhary

Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 μM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 μM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 μM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 μM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 μM), decreased ROS production (IC50 = 14.63 ± 3.18 μM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 μM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.


Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1474
Author(s):  
Shiau-Mei Chen ◽  
Siow-Wey Hee ◽  
Shih-Yun Chou ◽  
Meng-Wei Liu ◽  
Che-Hong Chen ◽  
...  

Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.


Proceedings ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 10
Author(s):  
Sasson

Hyperglycemia and hyperlipidemia synergistically and adversely impair insulin secretion and ultimately lead to pancreatic beta cell decomposition. We found that both nutrient overload conditions displace arachidonic and linoleic acids from membrane phospholipids and subject them to free radical-mediated peroxidation and generation of advanced lipid peroxidation end products (ALEs), of which the aldehyde 4-hydroxy-2-nonenal (4-HNE) is prominent. When present at high levels this electrophilic molecule binds covalently to nucleophilic moieties in proteins, phospholipids and nucleic acid, modifies their structure and function and leads to severe cellular dysfunction and apoptosis. However, when present at low and unharmful levels this same molecule activates the nuclear receptor PPARδ and augments insulin secretion. The level of endogenous 4-HNE is determined by the extent of lipid peroxidation on one hand, and by enzymatic neutralization of the aldehyde, on the other. The latter step is mediated by enzymatic processes of which the transformation of the aldehyde to the corresponding inactive carboxylic derivative 4-hydroxy-2-nonenoic acid (4-HNA) is significant. The enzyme responsible for this transformation, which belongs to the large family of aldehyde dehydrogenases and selectively neutralizes fatty acid-derived aldehydes, is ALDH3A2, which is also known as fatty aldehyde dehydrogenase (FALDH). Consequently, we hypothesized that the expression level and function of ALDH3A2 may determine the fate of beta cells under nutrient overload conditions: insufficient neutralization of 4-HNE by the enzyme will lead to cell demise, whereas increased expression and function will extend the adaptive response of beta cells. This adaptive response that is characterized with increased insulin secretion enables effective storage of the nutrient surplus in peripheral tissues and organs while minimizing the dire consequences of the nutrient overload. We aimed at investigating the expression pattern of ALDH3A2 in pancreatic beta cells (the INS-1E cell line) under hyperglycemic condition without or with supplementation with saturated fatty acids (e.g., palmitic acid). Our results show significant glucose- and palmitic acid-dependent induction of ALDH3A2 expression in the cells. We also found that the transformation of palmitic acid (16:1) to mono-unsaturated palmitoleic acid (16:1, cis 9) by the enzyme Stearoyl-CoA desaturase-1 (SCD1) decreased the burden of the lipid stress on the cells and abrogated the stimulus for the induction of ALDH3A2. Preliminary experiments indicated that the upregulation of the induction of ALDH3A2 was partly induced by PPARδ. These findings correlate to our previous discovery that the hormetic effects of 4HNE were mediated via activation of this nuclear receptor. In summary, this study assigns a central role to the enzyme ALDH3A2 in the protective mechanism beta cells employ to mitigate detrimental effects of ALEs, and divert them into hormetic agents, that by feedback mechanism through PPARδ increase ALDH3A2 expression.


2021 ◽  
Vol 13 (600) ◽  
pp. eabb1038
Author(s):  
Wing Yan So ◽  
Wai Nam Liu ◽  
Adrian Kee Keong Teo ◽  
Guy A. Rutter ◽  
Weiping Han

The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element–binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus–mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function.


2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Alex J Matsuda ◽  
Ana I Pinheiro ◽  
Andreia Amaral ◽  
Margarida Gama-Carvalho ◽  
Luís Rosário ◽  
...  

In recent years stem and progenitor cells have been identified in the heart, changing our understanding and therapeutic approach of heart disease. These cells can proliferate and differentiate in vitro into beating cardiomyocytes, endothelial and vascular smooth muscle cells, providing the potential for tissue regeneration and repair. microRNAs (miRs) have been identified as master switches controlling proliferation and differentiation, and in particular as key regulators of stem cells and cardiac development and function. Modulation of miR-regulated gene expression networks holds the potential to control cell fate and proliferation, with predictable biotechnological and therapeutic applications. We have characterized the expression profile of a subset of 100 miRs with reported functions in stem cell and tissue differentiation in mouse Sca1+ cardiac progenitor cells (CPCs). CPC miR expression profiles were compared with bone marrow mesenchymal stem cells (MSCs) and mouse embryonic heart (E=9) to obtain insights into the origins and function of this rare cell population. Within the miR panel that was studied, a subset with relative high expression levels in CPCs was identified, which may act as negative regulators of differentiation and proliferation. Although the overall expression profile of Sca1+ CPCs is closer to BM-MSCs, the most highly expressed miRs in CPCs are distinctive and predicted to target key genes involved in the control of cell proliferation and adhesion, vascular function and cardiomyocyte differentiation. Our results provide novel insights into the gene expression networks active in CPCs, which will now be explored in functional studies to identify key regulators of proliferation and differentiation.


2021 ◽  
Vol 22 (3) ◽  
pp. 1000
Author(s):  
Pauline Chabosseau ◽  
Guy A. Rutter ◽  
Steven J. Millership

Diabetes mellitus now affects more than 400 million individuals worldwide, with significant impacts on the lives of those affected and associated socio-economic costs. Although defects in insulin secretion underlie all forms of the disease, the molecular mechanisms which drive them are still poorly understood. Subsets of specialised beta cells have, in recent years, been suggested to play critical roles in “pacing” overall islet activity. The molecular nature of these cells, the means through which their identity is established and the changes which may contribute to their functional demise and “loss of influence” in both type 1 and type 2 diabetes are largely unknown. Genomic imprinting involves the selective silencing of one of the two parental alleles through DNA methylation and modified imprinted gene expression is involved in a number of diseases. Loss of expression, or loss of imprinting, can be shown in mouse models to lead to defects in beta cell function and abnormal insulin secretion. In the present review we survey the evidence that altered expression of imprinted genes contribute to loss of beta cell function, the importance of beta cell heterogeneity in normal and disease states, and hypothesise whether there is a direct link between the two.


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