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Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1. 胰岛内胰高血糖素样肽-1存在及其潜在作用的证据。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2021-03-04 Epub Date: 2021-03-16 DOI: 10.1080/19382014.2021.1889941
Scott A Campbell, Janyne Johnson, Peter E Light

Glucagon-Like Peptide-1 (GLP-1) is an important peptide hormone secreted by L-cells in the gastrointestinal tract in response to nutrients. It is produced by the differential cleavage of the proglucagon peptide. GLP-1 elicits a wide variety of physiological responses in many tissues that contribute to metabolic homeostasis. For these reasons, therapies designed to either increase endogenous GLP-1 levels or introduce exogenous peptide mimetics are now widely used in the management of diabetes. In addition to GLP-1 production from L-cells, recent reports suggest that pancreatic islet alpha cells may also synthesize and secrete GLP-1. Intra-islet GLP-1 may therefore play an unappreciated role in islet health and glucose regulation, suggesting a potential functional paracrine role for islet-derived GLP-1. In this review, we assess the current literature from an islet-centric point-of-view to better understand the production, degradation, and actions of GLP-1 within the endocrine pancreas in rodents and humans. The relevance of intra-islet GLP-1 in human physiology is discussed regarding the potential role of intra-islet GLP-1 in islet health and dysfunction.

胰高血糖素样肽-1 (Glucagon-Like peptide -1, GLP-1)是胃肠道l细胞对营养物质反应时分泌的一种重要肽激素。它是由胰高血糖素前肽的差异裂解产生的。GLP-1在许多组织中引起各种各样的生理反应,有助于代谢稳态。由于这些原因,旨在增加内源性GLP-1水平或引入外源性肽模拟物的疗法现在广泛用于糖尿病的治疗。除了l细胞产生GLP-1外,最近的报道表明胰岛α细胞也可能合成和分泌GLP-1。因此,胰岛内GLP-1可能在胰岛健康和葡萄糖调节中发挥未被认识到的作用,这表明胰岛来源的GLP-1可能具有潜在的功能旁分泌作用。在这篇综述中,我们从胰岛为中心的角度评估了目前的文献,以更好地了解GLP-1在啮齿动物和人类内分泌胰腺中的产生、降解和作用。关于胰岛内GLP-1在胰岛健康和功能障碍中的潜在作用,讨论了胰岛内GLP-1在人体生理学中的相关性。
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引用次数: 6
Protein kinase C-θ knockout decreases serum IL-10 levels and inhibits insulin secretion from islet β cells. 蛋白激酶C-θ敲除可降低血清IL-10水平,抑制胰岛β细胞分泌胰岛素。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2021-03-04 Epub Date: 2021-03-09 DOI: 10.1080/19382014.2021.1890963
Feng Hong, Yang Yang, Baiyi Chen, Peng Li, Guoguang Wang, Yuxin Jiang

Various subtypes of protein kinase C (PKC) are expressed in islet β cells and regulate β cell proliferation and survival. PKC-θ is distributed in the immune system and promotes the secretion of IL-10, which manifests a critical role in the onset of diabetes, by the immune cells. However, the role of PKC-θ in islets has not been concerned. In the present study, we investigated the role of PKC-θ in the protection of islet β cells and insulin secretion. Fasting glucose and insulin measurement, glucose tolerant test, immunofluorescence, and ELISA were conducted to study the influence of PKC-θ knockout on islet β cell survival and function, and explore the mechanism underlying this regulation. PKC-θ knockout mice at 2 weeks manifested normal serum insulin levels, glucose tolerance, and β cell mass. Knockout mice at 8 weeks show decreased β cell mass, but manifested normal insulin levels and glucose tolerance. Knockout mice at 16 weeks manifested impaired glucose tolerance, β cell mass, and decreased glucose stimulated insulin secretion. Furthermore, knockout mice manifested decreased serum IL-10 level compared with normal mice since 2 weeks. IL-10 injection into knockout mice improved glucose tolerance, serum insulin level, and reduced β cell mass, and IL-10 administration into cultured pancreatic tissue increased glucose stimulated insulin secretion. PKC-θ knockout decreases the secretion of IL-10, reduces β cell mass and insulin secretion in pancreatic islets. The present study illuminates the critical role of PKC-θ in protecting the survival and function of islet β cells.

多种蛋白激酶C (PKC)亚型在胰岛β细胞中表达,并调节β细胞的增殖和存活。PKC-θ分布于免疫系统,促进免疫细胞分泌IL-10, IL-10在糖尿病的发病中起着关键作用。然而,PKC-θ在胰岛中的作用尚未得到关注。在本研究中,我们研究了PKC-θ在保护胰岛β细胞和胰岛素分泌中的作用。通过空腹血糖和胰岛素测定、糖耐量试验、免疫荧光、ELISA等方法研究PKC-θ敲除对胰岛β细胞存活和功能的影响,并探讨其调控机制。2周时,PKC-θ基因敲除小鼠血清胰岛素水平、葡萄糖耐量和β细胞质量均正常。8周敲除小鼠β细胞质量下降,但胰岛素水平和葡萄糖耐量正常。16周敲除小鼠表现出糖耐量、β细胞质量受损,葡萄糖刺激胰岛素分泌减少。与正常小鼠相比,基因敲除小鼠血清IL-10水平从2周开始下降。敲除小鼠注射IL-10可改善葡萄糖耐量、血清胰岛素水平,减少β细胞质量,培养胰腺组织注射IL-10可增加葡萄糖刺激胰岛素分泌。敲除PKC-θ可降低胰岛IL-10分泌,减少β细胞质量和胰岛素分泌。本研究阐明了PKC-θ在保护胰岛β细胞存活和功能中的关键作用。
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引用次数: 0
Failure mode and effect analysis in human islet isolation: from the theoretical to the practical risk. 人胰岛隔离的失效模式及影响分析:从理论风险到实践风险。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2021-03-04 Epub Date: 2021-02-22 DOI: 10.1080/19382014.2020.1856618
Quentin Perrier, Vanessa Lavallard, Nadine Pernin, Charles-Henri Wassmer, David Cottet-Dumoulin, Fanny Lebreton, Kevin Bellofatto, Axel Andres, Ekaterine Berishvili, Domenico Bosco, Thierry Berney, Géraldine Parnaud

This study aimed to assess the global mapping risk of human islet isolation, using a failure mode and effect analysis (FMEA), and highlight the impact of quality assurance procedures on the risk level of criticality. Risks were scored using the risk priority number (RPN) scoring method. The risk level of criticality was made based on RPN and led to risk classification (low to critical). A raw risk analysis and a risk control analysis (with control means and quality assurance performance) were undertaken. The process of human islet isolation was divided into 11 steps, and 230 risks were identified. Analysis of the highest RPN of each of the 11 steps showed that the 4 highest risks were related to the pancreas digestion and islet purification stages. After implementation of reduction measures and controls, critical and severe risks were reduced by 3-fold and by 2-fold, respectively, so that 90% of risks could be considered as low to moderate. FMEA has proven to be a powerful approach for the identification of weaknesses in the islet isolation processes. The results demonstrated the importance of staff qualification and continuous training and supported the contribution of the quality assurance system to risk reduction.

本研究旨在利用失效模式和效应分析(FMEA)评估人类胰岛隔离的全球制图风险,并强调质量保证程序对临界风险水平的影响。采用风险优先级数(RPN)评分法对风险进行评分。在RPN的基础上确定了临界风险等级,并进行了从低到临界的风险分类。进行了原始风险分析和风险控制分析(包括控制手段和质量保证绩效)。将胰岛分离过程分为11个步骤,确定了230个风险。对11个步骤中最高RPN的分析显示,4个最高风险与胰腺消化和胰岛净化阶段有关。在实施减少措施和控制后,临界和严重风险分别降低了3倍和2倍,因此90%的风险可以被认为是低至中等。FMEA已被证明是识别孤岛隔离过程中的弱点的有力方法。结果表明了员工资格和持续培训的重要性,并支持了质量保证体系对降低风险的贡献。
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引用次数: 0
Culture, differentiation, and transduction of mouse E12.5 pancreatic spheres: an in vitro model for the secondary transition of pancreas development. 小鼠E12.5胰腺球体的培养、分化和转导:胰腺发育继发性转变的体外模型。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2021-03-04 Epub Date: 2021-03-01 DOI: 10.1080/19382014.2020.1863723
Lukas Huijbregts, Virginie Aiello, Andrea Soggia, Philippe Ravassard, Latif Rachdi, Raphaël Scharfmann, Olivier Albagli

During the secondary transition of rodent pancreatic development, mainly between E12.5 and E15.5 in mice, exocrine and endocrine populations differentiate from pancreatic progenitors. Here we describe an experimental system for its study in vitro. First, we show that spheres derived from dissociated E12.5 mouse pancreases differentiate within 7 days into most pancreatic exocrine and endocrine cell types, including beta cells. The proportion and spatial repartition of the different endocrine populations mirror those observed during normal development. Thus, dissociation and culture do not impair the developmental events affecting pancreatic progenitors during the secondary transition. Moreover, dissociated cells from mouse E12.5 pancreas were transduced with ecotropic MLV-based retroviral vectors or, though less efficiently, with a mixture of ALV(A)-based retroviral vectors and gesicles containing the TVA (Tumor Virus A) receptor. As an additional improvement, we also created a transgenic mouse line expressing TVA under the control of the 4.5 kB pdx1 promoter (pdx1-TVA). We demonstrate that pancreatic progenitors from dissociated pdx1-TVA pancreas can be specifically transduced by ALV(A)-based retroviral vectors. Using this model, we expressed an activated mutant of the YAP transcriptional co-activator in pancreatic progenitors. These experiments indicate that deregulated YAP activity reduces endocrine and exocrine differentiation in the resulting spheres, confirming and extending previously published data. Thus, our experimental model recapitulates in vitro the crucial developmental decisions arising at the secondary transition and provides a convenient tool to study their genetic control.

在啮齿动物胰腺发育的二次过渡期间,主要是在小鼠E12.5 - E15.5之间,外分泌和内分泌种群从胰腺祖细胞分化。在这里,我们描述了一个体外研究的实验系统。首先,我们发现从游离的E12.5小鼠胰腺中提取的球体在7天内分化为大多数胰腺外分泌和内分泌细胞类型,包括β细胞。不同内分泌种群的比例和空间再分配反映了正常发育时期的情况。因此,分离和培养不会损害继发性转变期间影响胰腺祖细胞的发育事件。此外,用基于生态型mlv的逆转录病毒载体或基于ALV(a)的逆转录病毒载体和含有TVA(肿瘤病毒a)受体的gesicles的混合物(尽管效率较低)转导小鼠E12.5胰腺的游离细胞。作为进一步的改进,我们还创建了一个在4.5 kB pdx1启动子(pdx1-TVA)控制下表达TVA的转基因小鼠系。我们证明了分离的pdx1-TVA胰腺的胰腺祖细胞可以被基于ALV(A)的逆转录病毒载体特异性转导。利用该模型,我们在胰腺祖细胞中表达了YAP转录共激活因子的激活突变体。这些实验表明,YAP活性的解除会减少所产生球体的内分泌和外分泌分化,证实并扩展了先前发表的数据。因此,我们的实验模型在体外概括了次生转变过程中产生的关键发育决定,并为研究其遗传控制提供了方便的工具。
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引用次数: 0
Cannabinoid receptors are differentially regulated in the pancreatic islets during the early development of metabolic syndrome. 在代谢综合征的早期发展过程中,大麻素受体在胰岛中受到差异调节。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2020-11-01 Epub Date: 2020-12-08 DOI: 10.1080/19382014.2020.1849927
Antonio Barajas-Martínez, Karina Bermeo, Lizbeth de la Cruz, Marina Martínez-Vargas, Ricardo Jesús Martínez-Tapia, David Erasmo García, Luz Navarro

The endocannabinoid system is found in tissues that regulate the glycemia, including adipose tissue, muscle, and pancreatic islets. Diet-induced metabolic syndrome changes the expression of the CB receptors in muscle, adipose tissue, and liver. However, it is poorly understood whether metabolic syndrome (MetS) affects the expression of CB receptors in pancreatic β cells. We analyzed the expression of CB receptors in pancreatic β cells under chronic high-sucrose diet (HSD)-induced MetS. Wistar rats fed an HSD as a model of MetS were used to investigate changes in cannabinoid receptors. After 8 weeks of treatment, we evaluated the appearance of the following MetS biomarkers: glucose intolerance, hyperinsulinemia, insulin resistance, hypertriglyceridemia, and an increase in visceral adiposity. To determine the presence of CB1 and CB2 receptors in pancreatic β cells, immunofluorescence of primary cell cultures and pancreatic sections was performed. For whole-islet quantification of membrane-bound CB1 and CB2 receptors, western-blotting following differential centrifugation was conducted. Our results revealed that an HSD treatment closely mimics the alterations seen in MetS. We observed that in primary cell culture, CB1 and CB2 receptors were expressed at a higher level in pancreatic β cells compared with non-β cells. MetS resulted in a reduction of CB1 in the islet, whereas abundant CB2 was observed after the treatment. CB1 and CB2 receptors are differentially expressed in pancreatic β cells during MetS development.

内源性大麻素系统存在于调节血糖的组织中,包括脂肪组织、肌肉和胰岛。饮食诱导代谢综合征改变肌肉、脂肪组织和肝脏中CB受体的表达。然而,代谢综合征(MetS)是否影响胰腺β细胞中CB受体的表达尚不清楚。我们分析了慢性高糖饮食(HSD)诱导的MetS下胰腺β细胞中CB受体的表达。用Wistar大鼠喂养HSD作为MetS模型,研究大麻素受体的变化。治疗8周后,我们评估了以下MetS生物标志物的出现:葡萄糖不耐受、高胰岛素血症、胰岛素抵抗、高甘油三酯血症和内脏脂肪增加。为了确定胰腺β细胞中CB1和CB2受体的存在,对原代细胞培养和胰腺切片进行了免疫荧光检测。对于全胰岛CB1和CB2受体的定量,在差速离心后进行western-blotting。我们的研究结果显示,HSD治疗与met的改变非常相似。我们观察到,在原代细胞培养中,与非β细胞相比,CB1和CB2受体在胰腺β细胞中的表达水平更高。MetS导致胰岛中CB1减少,而治疗后观察到丰富的CB2。CB1和CB2受体在met发育过程中在胰腺β细胞中差异表达。
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引用次数: 1
Transplantation of rat pancreatic islets vitrified-warmed on the nylon mesh device and the silk fibroin sponge disc. 尼龙网片和丝素海绵盘玻璃化加热大鼠胰岛移植。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2020-11-01 Epub Date: 2020-12-08 DOI: 10.1080/19382014.2020.1849928
Kenyu Nakayama-Iwatsuki, Takahiro Yamanaka, Jun Negishi, Junki Teshima, Yasushi Tamada, Masumi Hirabayashi, Shinichi Hochi

We report the adaptability of rat islets vitrified-warmed on nylon mesh (NM) device or silk fibroin (SF) sponge disc for the normalization of the blood glucose level in rat models of diabetes. One-hundred rat islets were cryopreserved according to a minimum volume cooling protocol on an NM device or a solid surface vitrification protocol on an SF sponge disc. The recovery rate (97.1% vs. 93.8%), the viability (77.9% vs. 74.4%), and the stimulation index (4.7 vs. 4.2) in glucose-stimulated insulin secretion (GSIS) assay of the post-warm islets were comparable between the NM vitrification and the SF vitrification groups. The viability and the stimulation index of the fresh control islets were identified to be 97.5% and 6.5, respectively. Eight hundred islets from the NM or the SF vitrification group or the fresh control group were transplanted beneath the kidney capsule of a streptozotocin-induced diabetic rat (blood glucose level > 350 mg/dl). Within 3 weeks after transplantation, the acquisition of euglycemia (< 200 mg/dl) was observed in recipient rats (80.0-83.3%). An intraperitoneal glucose tolerance test on Day-30 and Day-60 showed similar 2-h responses to the glucose uptake of cured rats among the compared groups. Moreover, the successful engraftment of transplants was confirmed by the Day-70 nephrectomy through the subsequent diabetes reversal and histological evaluation. Thus, large quantities of rat islets vitrified-warmed on an NM device or an SF sponge disc were proven to be fully functional both in vitro and in vivo, due to the GSIS and syngeneic transplantation, respectively.

我们报道了在尼龙网(NM)装置或丝素(SF)海绵盘上玻璃化加热的大鼠胰岛对糖尿病模型大鼠血糖水平正常化的适应性。100个大鼠胰岛按照NM设备上的最小体积冷却方案或SF海绵盘上的固体表面玻璃化方案冷冻保存。温后胰岛葡萄糖刺激胰岛素分泌(GSIS)测定的恢复率(97.1% vs. 93.8%)、活力(77.9% vs. 74.4%)和刺激指数(4.7 vs. 4.2)在纳米玻璃化组和SF玻璃化组之间具有可比性。新鲜对照胰岛的活力和刺激指数分别为97.5%和6.5。取纳米、SF玻璃化组和新鲜对照组胰岛800个移植于链脲佐菌素诱导的糖尿病大鼠(血糖水平> 350mg /dl)肾囊下。移植后3周内,受体大鼠(80.0 ~ 83.3%)血糖恢复正常(< 200 mg/dl)。第30天和第60天的腹腔葡萄糖耐量试验显示,对照组中治愈大鼠的2小时葡萄糖摄取反应相似。此外,通过随后的糖尿病逆转和组织学评估,在第70天的肾脏切除术中证实了移植的成功。因此,在NM装置或SF海绵盘上玻璃化加热的大量大鼠胰岛,分别由于GSIS和同基因移植,在体外和体内都被证明具有完全的功能。
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引用次数: 4
Reconstructing human pancreatic islet architectures using computational optimization. 利用计算优化重建人类胰岛结构。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2020-11-01 Epub Date: 2020-10-22 DOI: 10.1080/19382014.2020.1823178
Gerardo J Félix-Martínez, Aurelio N Mata, J Rafael Godínez-Fernández

We outline a general methodology based on computational optimization and experimental data to reconstruct human pancreatic islet architectures. By using the nuclei coordinates of islet cells obtained through DAPI staining, cell types identified by immunostaining, and cell size distributions estimated from capacitance measurements, reconstructed islets composed of non-overlapping spherical cells were obtained through an iterative optimization procedure. In all cases, the reconstructed architectures included >99% of the experimental identified cells, each of them having a radius within the experimentally reported ranges. Given the wide use of mathematical modeling for the study of pancreatic cells, and recently, of cell-cell interactions within the pancreatic islets, the methodology here proposed, also capable of identifying cell-to-cell contacts, is aimed to provide with a framework for modeling and analyzing experimentally-based pancreatic islet architectures.

我们概述了一种基于计算优化和实验数据的一般方法来重建人类胰岛结构。利用DAPI染色获得的胰岛细胞核坐标、免疫染色鉴定的细胞类型和电容测量估计的细胞大小分布,通过迭代优化程序获得非重叠球形细胞组成的重建胰岛。在所有情况下,重建的结构包括>99%的实验识别细胞,每个细胞的半径都在实验报告的范围内。鉴于数学建模在胰腺细胞研究中的广泛应用,以及最近胰岛内细胞间相互作用的研究,本文提出的方法也能够识别细胞间的接触,旨在为基于实验的胰岛结构建模和分析提供一个框架。
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引用次数: 7
The role of α-ketoglutarate and the hypoxia sensing pathway in the regulation of pancreatic β-cell function. α-酮戊二酸及其缺氧感应通路在胰腺β细胞功能调节中的作用。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2020-09-02 DOI: 10.1080/19382014.2020.1802183
M Hoang, J W Joseph

Anaplerosis and the associated mitochondrial metabolite transporters generate unique cytosolic metabolic signaling molecules that can regulate insulin release from pancreatic β-cells. It has been shown that mitochondrial metabolites, transported by the citrate carrier (CIC), dicarboxylate carrier (DIC), oxoglutarate carrier (OGC), and mitochondrial pyruvate carrier (MPC) play a vital role in the regulation of glucose-stimulated insulin secretion (GSIS). Metabolomic studies on static and biphasic insulin secretion, suggests that several anaplerotic derived metabolites, including α-ketoglutarate (αKG), are strongly associated with nutrient regulated insulin secretion. Support for a role of αKG in the regulation of insulin secretion comes from studies looking at αKG dependent enzymes, including hypoxia-inducible factor-prolyl hydroxylases (PHDs) in clonal β-cells, and rodent and human islets. This review will focus on the possible link between defective anaplerotic-derived αKG, PHDs, and the development of type 2 diabetes (T2D).

逆转和相关的线粒体代谢物转运体产生独特的胞质代谢信号分子,可以调节胰腺β细胞的胰岛素释放。研究表明,通过柠檬酸盐载体(CIC)、二羧酸盐载体(DIC)、氧葡萄糖酸盐载体(OGC)和线粒体丙酮酸盐载体(MPC)运输的线粒体代谢物在葡萄糖刺激胰岛素分泌(GSIS)的调节中起着至关重要的作用。静态和双相胰岛素分泌的代谢组学研究表明,包括α-酮戊二酸酯(αKG)在内的几种非突变衍生代谢物与营养调节的胰岛素分泌密切相关。对αKG依赖性酶的研究支持了αKG在胰岛素分泌调节中的作用,包括克隆β细胞、啮齿动物和人类胰岛中的缺氧诱导因子-脯氨酸羟化酶(ph)。本文将重点讨论过敏性αKG、博士缺陷与2型糖尿病(T2D)发展之间的可能联系。
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引用次数: 5
Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish. 靶向多胺生物合成刺激斑马鱼β细胞再生。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2020-09-02 Epub Date: 2020-07-25 DOI: 10.1080/19382014.2020.1791530
Morgan A Robertson, Leah R Padgett, Jonathan A Fine, Gaurav Chopra, Teresa L Mastracci

Type 1 diabetes (T1D) is a disease characterized by destruction of the insulin-producing beta cells. Currently, there remains a critical gap in our understanding of how to reverse or prevent beta cell loss in individuals with T1D. Previous studies in mice discovered that pharmacologically inhibiting polyamine biosynthesis using difluoromethylornithine (DFMO) resulted in preserved beta cell function and mass. Similarly, treatment of non-obese diabetic mice with the tyrosine kinase inhibitor Imatinib mesylate reversed diabetes. The promising findings from these animal studies resulted in the initiation of two separate clinical trials that would repurpose either DFMO (NCT02384889) or Imatinib (NCT01781975) and determine effects on diabetes outcomes; however, whether these drugs directly stimulated beta cell growth remained unknown. To address this, we used the zebrafish model system to determine pharmacological impact on beta cell regeneration. After induction of beta cell death, zebrafish embryos were treated with either DFMO or Imatinib. Neither drug altered whole-body growth or exocrine pancreas length. Embryos treated with Imatinib showed no effect on beta cell regeneration; however, excitingly, DFMO enhanced beta cell regeneration. These data suggest that pharmacological inhibition of polyamine biosynthesis may be a promising therapeutic option to stimulate beta cell regeneration in the setting of diabetes.

1型糖尿病(T1D)是一种以产生胰岛素的β细胞破坏为特征的疾病。目前,我们对如何逆转或预防T1D患者的β细胞损失的理解仍然存在一个关键的空白。先前对小鼠的研究发现,使用二氟甲基鸟氨酸(DFMO)从药理学上抑制多胺的生物合成,可以保留β细胞的功能和质量。同样,用酪氨酸激酶抑制剂甲磺酸伊马替尼治疗非肥胖糖尿病小鼠可以逆转糖尿病。这些有希望的动物研究结果导致启动了两项独立的临床试验,将重新定位DFMO (NCT02384889)或伊马替尼(NCT01781975),并确定对糖尿病结局的影响;然而,这些药物是否直接刺激β细胞生长仍然未知。为了解决这个问题,我们使用斑马鱼模型系统来确定药物对β细胞再生的影响。诱导β细胞死亡后,用DFMO或伊马替尼处理斑马鱼胚胎。两种药物均未改变全身生长或外分泌胰腺长度。用伊马替尼处理的胚胎对β细胞再生没有影响;然而,令人兴奋的是,DFMO增强了β细胞再生。这些数据表明,药物抑制多胺生物合成可能是一种有希望的治疗选择,以刺激糖尿病患者的β细胞再生。
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引用次数: 6
Melatonin protects INS-1 pancreatic β-cells from apoptosis and senescence induced by glucotoxicity and glucolipotoxicity. 褪黑素对糖毒性和糖脂毒性诱导的INS-1胰腺β-细胞凋亡和衰老具有保护作用。
IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2020-07-03 Epub Date: 2020-07-16 DOI: 10.1080/19382014.2020.1783162
Yu Hee Lee, Hye Sook Jung, Min Jeong Kwon, Jung Eun Jang, Tae Nyun Kim, Soon Hee Lee, Mi-Kyung Kim, Jeong Hyun Park

Introduction: Melatonin is a hormone known as having very strong anti-oxidant property. Senescence is a biological state characterized by the loss of cell replication and the changes consisting of a pro-inflammatory phenotype, leading to Senescence Associated Secretory Phenotype (SASP) which is now regarded as one of the fundamental processes of many degenerative diseases. Increased cell division count induces cell senescence via DNA damage in response to elevated Reactive Oxygen Species (ROS). We wanted to test whether melatonin could reduce apoptosis and stress induced premature pancreatic β-cell senescence induced by glucotoxicity and glucolipotoxicity.

Materials and method: Cultured rodent pancreatic β-cell line (INS-1 cell) was used. Glucotoxicity (HG: hyperglycemia) and glucolipotoxicity (HGP: hyperglycemia with palmitate) were induced by hyperglycemia and the addition of palmitate. The degrees of the senescence were measured by SA-β-Gal and P16lnk4A staining along with the changes of cell viabilities, cell cycle-related protein and gene expressions, endogenous anti-oxidant defense enzymes, and Glucose Stimulated Insulin Secretion (GSIS), before and after melatonin treatment.

Results: Cultured INS-1 cells in HG and HGP conditions revealed accelerated senescence, increased apoptosis, cell cycle arrest, compromised endogenous anti-oxidant defense, and impaired glucose-stimulated insulin secretion. Melatonin decreased apoptosis and expressions of proteins related to senescence, increase the endogenous anti-oxidant defense, and improved glucose-stimulated insulin secretion.

Conclusion: Melatonin protected pancreatic β-cell from apoptosis, decreased expressions of the markers related to the accelerated senescence, and improved the biological deteriorations induced by glucotoxicity and glucolipotoxicity.

简介:褪黑激素是一种被认为具有很强抗氧化特性的激素。衰老是一种以细胞复制丧失和促炎表型变化为特征的生物学状态,导致衰老相关分泌表型(Senescence Associated Secretory phenotype, SASP),目前被认为是许多退行性疾病的基本过程之一。增加细胞分裂计数诱导细胞衰老通过DNA损伤响应升高的活性氧(ROS)。我们想测试褪黑素是否可以减少由糖毒性和糖脂毒性引起的细胞凋亡和应激诱导的胰腺β细胞过早衰老。材料和方法:采用培养的啮齿动物胰腺β细胞系(INS-1细胞)。高血糖和添加棕榈酸盐诱导糖毒性(HG:高血糖)和糖脂毒性(HGP:伴有棕榈酸盐的高血糖)。通过SA-β-Gal和P16lnk4A染色检测褪黑素处理前后细胞活力、细胞周期相关蛋白和基因表达、内源性抗氧化防御酶、葡萄糖刺激胰岛素分泌(GSIS)的变化,观察衰老程度。结果:在HG和HGP条件下培养的INS-1细胞表现出衰老加速、凋亡增加、细胞周期阻滞、内源性抗氧化防御受损和葡萄糖刺激的胰岛素分泌受损。褪黑素可以减少细胞凋亡和衰老相关蛋白的表达,增强内源性抗氧化防御,改善葡萄糖刺激的胰岛素分泌。结论:褪黑素可保护胰腺β细胞免于凋亡,降低加速衰老相关标志物的表达,改善糖毒性和糖脂毒性引起的生物学恶化。
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引用次数: 8
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