β-Cell gene expression stress signatures in types 1 and 2 diabetes

IF 3 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Xiaoyan Yi, Decio L. Eizirik
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While T1D is a disease of “mistaken identity,” where the immune system attacks and destroys pancreatic β-cells in the context of islet inflammation (insulitis),<span><sup>1</sup></span> T2D is associated with sedentary lifestyles and high-fat diets, typically involving ineffective use of insulin and progressive loss of β-cell function.<span><sup>1</sup></span> Both diseases result from multifaceted interactions between genetic and environmental factors, with β-cell failure as the core mechanism of pathogenesis.</p><p>In T1D, the disease arises from a complex interaction between immune cells and β-cells, involving chemokine and cytokine release and signals from stressed or dying β-cells that attract and activate immune cells to the islets and lead to β-cell apoptosis.<span><sup>2</sup></span> Beyond the destruction of β-cells by the immune system, it is now accepted that stress and impaired function of these cells significantly contribute to the onset and progression of the disease.<span><sup>1-3</sup></span> In T2D, the disease is driven by an interplay between insulin resistance and β-cell dysfunction in genetically susceptible individuals, with metabolic stress and perhaps also inflammation impairing insulin secretion and eventually β-cell survival, although to a less degree than in T1D.<span><sup>1, 4, 5</sup></span></p><p>The complexity of diabetes pathogenesis makes it very difficult to identify specific causes of the disease, which hampers the development of adequate therapies to protect β-cells and thus prevent disease. This difficulty was well described by Tolstoy, in his masterpiece “War and Peace,” published 1869 (in this case addressing the Napoleonic war against tsarist Russia): “…the impulse to seek causes is innate in the soul of man. And the human intellect, with no inkling on the immense variety and complexity of circumstances conditioning a phenomena, any one of which may be separately conceived of as the cause of it, snatches the first and most easily understood approximation, and says here is the cause.” In the context of pathophysiology, this had led to the simplistic view of “one gene, one protein, one disease.” However, with the sequencing of the human genome and the subsequent advent of omics technologies that allow interrogating the whole system in a parallel and often also in a sequential way, our understanding of complex diseases changed: we now focus on the dysfunction of gene and transcription factor networks and of post-transcriptional and post-translational mechanisms.</p><p>The advent of single-cell RNA sequencing (scRNA-seq) has provided a new tool for dissecting the molecular intricacies underlying pancreatic islet cells stress and thus addressing mechanisms of disease closer to its real “immense variety and complexity of circumstances.” A recent study by Maestas et al. focused on β-cell stress by utilizing in vitro models to investigate the effects of ER stress inducers (thapsigargin, brefeldin A) and inflammatory cytokines (IFNγ, IL1β, TNFα, and their combination) on β-cells, using islets from five donors for the scRNA-seq analysis.<span><sup>6</sup></span> This study provided very interesting information, but the limited number of donors and the use of in vitro stress conditions to model T1D and T2D may have not fully captured the in vivo disease context.</p><p>To further investigate the stress signatures potentially present in the human disease, we presently analyzed data from the Human Pancreas Analysis Program (HPAP).<span><sup>7, 8</sup></span> The HPAP provides an extensive public database with scRNA-seq data from islets from non-diabetic individuals or individuals affected by T1D or T2D, offering a valuable resource to study disease-specific transcriptional profiles of β-cells.</p><p>We thus re-analyzed scRNA-seq data from the HPAP database up to 12.2023, which includes 10X Genomics data for islets from 27 non-diabetic, 7 T1D, and 10 T2D individuals, using our previously described pipeline.<span><sup>9</sup></span> We employed an indexed gene signature scoring method,<span><sup>9-11</sup></span> to profile six sets of β-cell stress signatures, namely, inflammation, senescence, autophagy, apoptosis, endoplasmic reticulum (ER) protein processing, and unfolded protein response (UPR). The gene signature for inflammation was collected from our previous study, which comprises 80 genes highly stimulated (i.e., &gt;3 fold) by IFN-α, IFN-γ, and IL-1β in human insulin-producing EndoC-βH1 cells.<span><sup>9</sup></span> The remaining five sets of gene signatures are derived from the Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases and included the following number of genes: 157 for cellular senescence; 146 for autophagy; 140 for apoptosis; 170 for ER protein processing; 92 for UPR.</p><p>A potential limitation for the present analysis is the diverse number of cells recovered from the three groups (15 281 for 27 non-diabetic controls, 585 for 7 T1D, and 1455 for 10 T2D), which is due to both the different number of donors and the inherent loss of β-cells in the course of diabetes (associated to the difficult of isolating islets from individuals affected by diabetes). In spite of this methodological limitation, our analysis revealed that all β-cell stress signatures were upregulated in both T1D and T2D, with T1D showing higher scores for all forms of stress (Figure 1). Notably, T1D β-cells exhibited a &gt;200% increase in the inflammation signature score as compared to T2D or non-diabetic controls. There was also a clear increase in the score signatures of senescence, autophagy, apoptosis and ER stress in β-cells from individuals affected by T1D compared to non-diabetic individuals (20%–43%), and only a mild (6%–27%) increase in β-cells from individuals affected by T2D compared to controls. These results confirm and extend the observations by Maestas et al.<span><sup>6</sup></span> that in both T1D and T2D β-cells experience multiple forms of stress, while emphasizing that β-cells in T1D undergo a more severe stress, which is in line with the faster and more massive β-cell loss in T1D as compared to T2D.<span><sup>5</sup></span></p><p>Proper insulin processing in the ER under metabolic stress conditions necessitates physiological and transient activation of the UPR, while prolonged and excessive activation (“terminal” UPR) can trigger cell death.<span><sup>5</sup></span> To understand the relationship between the UPR and apoptosis or cellular senescence in diabetes, we conducted a correlation analysis using the above described signature index scores. There was a significant positive correlation between the UPR and both apoptosis and cellular senescence in T1D and T2D (Figure 2), with the strongest correlation observed in T1D (Figure 2A), which is in line with the detection by histology of ER stress markers in islets of individuals affected by T1D.<span><sup>12</sup></span> To further understand the causality of apoptosis, we developed a multiple regression model with the following formulations: apoptosis ~ inflammation + autophagy + cellular senescence + UPR. We found that these stress signaling pathways together effectively predict cell death signature in T1D (<i>R</i><sup>2</sup> = 0.80) and T2D (<i>R</i><sup>2</sup> = 0.75).</p><p>The implications of ours and Maestas et al.<span><sup>6</sup></span> findings are twofold. First, targeting β-cell stress pathways—particularly inflammation, ER stress, and senescence—may offer a therapeutic strategy for T1D and, to a less extent, to T2D. These observations, however, must be considered with caution as for instance gene signatures alone are not sufficient to identify senescence and many markers of the secretory phenotype of senescence, downstream of the transcription factors NF-κB and STATs,<span><sup>13</sup></span> are also part of the autoimmune-induced insulitis,<span><sup>2, 5</sup></span> making it difficult to discriminate between senescence- and inflammation-induced signatures in T1D.</p><p>In support for a role of components of senescence contributing to T1D is the demonstration that targeted elimination of senescent β-cells prevent diabetes in non-obese (NOD) diabetic mice,<span><sup>14</sup></span> and the fact that an early senescence signature is present in the residual β-cells of patients with T1D.<span><sup>15</sup></span></p><p>The present analysis also indicated a positive correlation between the UPR and apoptosis, as well as between the UPR and cellular senescence in T1D and, to a less extent, T2D. Excessive and/or prolonged UPR contributes to the development of diabetes by promoting pancreatic β-cell loss and insulin resistance.<span><sup>16</sup></span> IRE1, one of the UPR's master regulators, induces β-cell apoptosis and degeneration at “terminal” ER stress level, while inhibition of IRE1 in mouse models protects β-cells and may provide therapeutic opportunities for diabetes.<span><sup>17</sup></span> Moreover, inhibition of another UPR regulator, namely the eIF2α kinase PERK, reverses the translation blockade present in stressed human islets and prevents diabetes in NOD mice.<span><sup>18</sup></span></p><p>Of interest, there is also crosstalk between the different β-cell stresses, as deletion of the UPR genes ATF6 and IRE1α in NOD mice before the onset of insulitis leads to a p21-driven early senescence phenotype that paradoxically reduces terminal β-cell senescence and the incidence of diabetes.<span><sup>15</sup></span> Future research should explore the interactions between the stress signaling pathways and their leading-edge genes discussed above, as well as their combined impact on β-cell function and survival across different types of diabetes.</p><p>This comment highlights the β-cell stress signatures in T1D and T2D, utilizing an index score method based on scRNA-seq data from 44 human islets donors. Key findings indicate that T1D (and to a less extent T2D) is characterized by elevated inflammatory stress and disturbances in multiple stress signaling pathways. Strong correlations was observed between the UPR, apoptosis, and cellular senescence. These results add relevant human disease information to the previous in vitro findings by Maestas et al.<span><sup>6</sup></span> and emphasize the relevance of studying gene signatures of affected human tissues in autoimmune or degenerative diseases in the search for better and more targeted therapies that address the disease at its real level of complexity.<span><sup>10, 19</sup></span></p><p>Decio L. Eizirik conceptualized the study, Xiaoyan Yi performed data analysis and drafted the manuscript. Decio L. Eizirik contributed by reviewing, editing, and adding content. Both authors approved the final version of the manuscript. Xiaoyan Yi and Decio L. Eizirik have contributed significantly and in keeping with the latest guidelines of International Committee of Medical Journal Editors. Xiaoyan Yi and Decio L. Eizirik serve as guarantors of this work.</p><p>Research by the authors is supported by grants from Breakthrough T1D (formerly JDRF International (3-SRA-2022-1201-S-B [1] and 3-SRA-2022-1201-S-B [2])); the National Institutes of Health - Human Islet Research Network Consortium on Beta Cell Death &amp; Survival from Pancreatic β-Cell Gene Networks to Therapy (HIRN-CBDS) (grant U01 DK127786); and the National Institutes of Health NIDDK grants, RO1DK126444 and RO1DK133881-01.</p><p>The authors declare no conflicts of interest related to this commentary.</p>","PeriodicalId":189,"journal":{"name":"Journal of Diabetes","volume":"16 11","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540585/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Diabetes","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/1753-0407.70026","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder that occurs when pancreatic β-cells can no longer produce enough insulin to maintain normal blood glucose levels. DM presently affects 10.5% of the world adult population. While T1D is a disease of “mistaken identity,” where the immune system attacks and destroys pancreatic β-cells in the context of islet inflammation (insulitis),1 T2D is associated with sedentary lifestyles and high-fat diets, typically involving ineffective use of insulin and progressive loss of β-cell function.1 Both diseases result from multifaceted interactions between genetic and environmental factors, with β-cell failure as the core mechanism of pathogenesis.

In T1D, the disease arises from a complex interaction between immune cells and β-cells, involving chemokine and cytokine release and signals from stressed or dying β-cells that attract and activate immune cells to the islets and lead to β-cell apoptosis.2 Beyond the destruction of β-cells by the immune system, it is now accepted that stress and impaired function of these cells significantly contribute to the onset and progression of the disease.1-3 In T2D, the disease is driven by an interplay between insulin resistance and β-cell dysfunction in genetically susceptible individuals, with metabolic stress and perhaps also inflammation impairing insulin secretion and eventually β-cell survival, although to a less degree than in T1D.1, 4, 5

The complexity of diabetes pathogenesis makes it very difficult to identify specific causes of the disease, which hampers the development of adequate therapies to protect β-cells and thus prevent disease. This difficulty was well described by Tolstoy, in his masterpiece “War and Peace,” published 1869 (in this case addressing the Napoleonic war against tsarist Russia): “…the impulse to seek causes is innate in the soul of man. And the human intellect, with no inkling on the immense variety and complexity of circumstances conditioning a phenomena, any one of which may be separately conceived of as the cause of it, snatches the first and most easily understood approximation, and says here is the cause.” In the context of pathophysiology, this had led to the simplistic view of “one gene, one protein, one disease.” However, with the sequencing of the human genome and the subsequent advent of omics technologies that allow interrogating the whole system in a parallel and often also in a sequential way, our understanding of complex diseases changed: we now focus on the dysfunction of gene and transcription factor networks and of post-transcriptional and post-translational mechanisms.

The advent of single-cell RNA sequencing (scRNA-seq) has provided a new tool for dissecting the molecular intricacies underlying pancreatic islet cells stress and thus addressing mechanisms of disease closer to its real “immense variety and complexity of circumstances.” A recent study by Maestas et al. focused on β-cell stress by utilizing in vitro models to investigate the effects of ER stress inducers (thapsigargin, brefeldin A) and inflammatory cytokines (IFNγ, IL1β, TNFα, and their combination) on β-cells, using islets from five donors for the scRNA-seq analysis.6 This study provided very interesting information, but the limited number of donors and the use of in vitro stress conditions to model T1D and T2D may have not fully captured the in vivo disease context.

To further investigate the stress signatures potentially present in the human disease, we presently analyzed data from the Human Pancreas Analysis Program (HPAP).7, 8 The HPAP provides an extensive public database with scRNA-seq data from islets from non-diabetic individuals or individuals affected by T1D or T2D, offering a valuable resource to study disease-specific transcriptional profiles of β-cells.

We thus re-analyzed scRNA-seq data from the HPAP database up to 12.2023, which includes 10X Genomics data for islets from 27 non-diabetic, 7 T1D, and 10 T2D individuals, using our previously described pipeline.9 We employed an indexed gene signature scoring method,9-11 to profile six sets of β-cell stress signatures, namely, inflammation, senescence, autophagy, apoptosis, endoplasmic reticulum (ER) protein processing, and unfolded protein response (UPR). The gene signature for inflammation was collected from our previous study, which comprises 80 genes highly stimulated (i.e., >3 fold) by IFN-α, IFN-γ, and IL-1β in human insulin-producing EndoC-βH1 cells.9 The remaining five sets of gene signatures are derived from the Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases and included the following number of genes: 157 for cellular senescence; 146 for autophagy; 140 for apoptosis; 170 for ER protein processing; 92 for UPR.

A potential limitation for the present analysis is the diverse number of cells recovered from the three groups (15 281 for 27 non-diabetic controls, 585 for 7 T1D, and 1455 for 10 T2D), which is due to both the different number of donors and the inherent loss of β-cells in the course of diabetes (associated to the difficult of isolating islets from individuals affected by diabetes). In spite of this methodological limitation, our analysis revealed that all β-cell stress signatures were upregulated in both T1D and T2D, with T1D showing higher scores for all forms of stress (Figure 1). Notably, T1D β-cells exhibited a >200% increase in the inflammation signature score as compared to T2D or non-diabetic controls. There was also a clear increase in the score signatures of senescence, autophagy, apoptosis and ER stress in β-cells from individuals affected by T1D compared to non-diabetic individuals (20%–43%), and only a mild (6%–27%) increase in β-cells from individuals affected by T2D compared to controls. These results confirm and extend the observations by Maestas et al.6 that in both T1D and T2D β-cells experience multiple forms of stress, while emphasizing that β-cells in T1D undergo a more severe stress, which is in line with the faster and more massive β-cell loss in T1D as compared to T2D.5

Proper insulin processing in the ER under metabolic stress conditions necessitates physiological and transient activation of the UPR, while prolonged and excessive activation (“terminal” UPR) can trigger cell death.5 To understand the relationship between the UPR and apoptosis or cellular senescence in diabetes, we conducted a correlation analysis using the above described signature index scores. There was a significant positive correlation between the UPR and both apoptosis and cellular senescence in T1D and T2D (Figure 2), with the strongest correlation observed in T1D (Figure 2A), which is in line with the detection by histology of ER stress markers in islets of individuals affected by T1D.12 To further understand the causality of apoptosis, we developed a multiple regression model with the following formulations: apoptosis ~ inflammation + autophagy + cellular senescence + UPR. We found that these stress signaling pathways together effectively predict cell death signature in T1D (R2 = 0.80) and T2D (R2 = 0.75).

The implications of ours and Maestas et al.6 findings are twofold. First, targeting β-cell stress pathways—particularly inflammation, ER stress, and senescence—may offer a therapeutic strategy for T1D and, to a less extent, to T2D. These observations, however, must be considered with caution as for instance gene signatures alone are not sufficient to identify senescence and many markers of the secretory phenotype of senescence, downstream of the transcription factors NF-κB and STATs,13 are also part of the autoimmune-induced insulitis,2, 5 making it difficult to discriminate between senescence- and inflammation-induced signatures in T1D.

In support for a role of components of senescence contributing to T1D is the demonstration that targeted elimination of senescent β-cells prevent diabetes in non-obese (NOD) diabetic mice,14 and the fact that an early senescence signature is present in the residual β-cells of patients with T1D.15

The present analysis also indicated a positive correlation between the UPR and apoptosis, as well as between the UPR and cellular senescence in T1D and, to a less extent, T2D. Excessive and/or prolonged UPR contributes to the development of diabetes by promoting pancreatic β-cell loss and insulin resistance.16 IRE1, one of the UPR's master regulators, induces β-cell apoptosis and degeneration at “terminal” ER stress level, while inhibition of IRE1 in mouse models protects β-cells and may provide therapeutic opportunities for diabetes.17 Moreover, inhibition of another UPR regulator, namely the eIF2α kinase PERK, reverses the translation blockade present in stressed human islets and prevents diabetes in NOD mice.18

Of interest, there is also crosstalk between the different β-cell stresses, as deletion of the UPR genes ATF6 and IRE1α in NOD mice before the onset of insulitis leads to a p21-driven early senescence phenotype that paradoxically reduces terminal β-cell senescence and the incidence of diabetes.15 Future research should explore the interactions between the stress signaling pathways and their leading-edge genes discussed above, as well as their combined impact on β-cell function and survival across different types of diabetes.

This comment highlights the β-cell stress signatures in T1D and T2D, utilizing an index score method based on scRNA-seq data from 44 human islets donors. Key findings indicate that T1D (and to a less extent T2D) is characterized by elevated inflammatory stress and disturbances in multiple stress signaling pathways. Strong correlations was observed between the UPR, apoptosis, and cellular senescence. These results add relevant human disease information to the previous in vitro findings by Maestas et al.6 and emphasize the relevance of studying gene signatures of affected human tissues in autoimmune or degenerative diseases in the search for better and more targeted therapies that address the disease at its real level of complexity.10, 19

Decio L. Eizirik conceptualized the study, Xiaoyan Yi performed data analysis and drafted the manuscript. Decio L. Eizirik contributed by reviewing, editing, and adding content. Both authors approved the final version of the manuscript. Xiaoyan Yi and Decio L. Eizirik have contributed significantly and in keeping with the latest guidelines of International Committee of Medical Journal Editors. Xiaoyan Yi and Decio L. Eizirik serve as guarantors of this work.

Research by the authors is supported by grants from Breakthrough T1D (formerly JDRF International (3-SRA-2022-1201-S-B [1] and 3-SRA-2022-1201-S-B [2])); the National Institutes of Health - Human Islet Research Network Consortium on Beta Cell Death & Survival from Pancreatic β-Cell Gene Networks to Therapy (HIRN-CBDS) (grant U01 DK127786); and the National Institutes of Health NIDDK grants, RO1DK126444 and RO1DK133881-01.

The authors declare no conflicts of interest related to this commentary.

1 型和 2 型糖尿病的 β 细胞基因表达应激特征。
本分析的一个潜在局限性是从三组中回收的细胞数量不同(27 个非糖尿病对照组回收了 15 281 个细胞,7 个 T1D 回收了 585 个细胞,10 个 T2D 回收了 1455 个细胞),这既是由于供体数量不同,也是由于糖尿病过程中 β 细胞的固有损失(与从糖尿病患者身上分离胰岛的困难有关)。尽管存在这种方法上的局限性,但我们的分析表明,T1D 和 T2D 的所有 β 细胞应激特征均上调,T1D 在所有形式的应激中得分更高(图 1)。值得注意的是,与 T2D 或非糖尿病对照组相比,T1D β 细胞的炎症特征得分增加了 200%。与非糖尿病患者相比,T1D患者的β细胞在衰老、自噬、细胞凋亡和ER应激方面的特征得分也明显增加(20%-43%),而与对照组相比,T2D患者的β细胞在衰老、自噬、细胞凋亡和ER应激方面的特征得分仅轻微增加(6%-27%)。这些结果证实并扩展了Maestas等人6 的观察结果,即T1D和T2D患者的β细胞都经历了多种形式的应激,同时强调T1D患者的β细胞经历了更严重的应激,这与T1D患者的β细胞比T2D患者损失得更快、更多是一致的。5 为了了解 UPR 与糖尿病患者细胞凋亡或细胞衰老之间的关系,我们利用上述特征指数得分进行了相关性分析。在 T1D 和 T2D 中,UPR 与细胞凋亡和细胞衰老之间存在明显的正相关性(图 2),在 T1D 中观察到的相关性最强(图 2A),这与组织学在 T1D 患者的胰岛中检测到的 ER 应激标记物相符12。我们发现,这些应激信号通路共同有效地预测了 T1D(R2 = 0.80)和 T2D(R2 = 0.75)的细胞死亡特征。首先,针对β细胞应激途径--尤其是炎症、ER应激和衰老--可能为T1D提供一种治疗策略,在一定程度上也可为T2D提供一种治疗策略。然而,这些观察结果必须谨慎考虑,因为仅靠基因特征不足以识别衰老,而且衰老分泌表型的许多标记物(转录因子 NF-κB 和 STATs 的下游标记物13 )也是自身免疫诱导的胰岛炎的一部分,2、5 因此很难区分 T1D 中衰老和炎症诱导的特征。有研究表明,有针对性地消除衰老的 β 细胞可预防非肥胖(NOD)糖尿病小鼠的糖尿病14 ,而且 T1D 患者残留的 β 细胞中存在早期衰老特征,这些都支持衰老成分在 T1D 中的作用15。目前的分析还表明,在 T1D 和 T2D 中,UPR 与细胞凋亡之间以及 UPR 与细胞衰老之间存在正相关,但 T2D 的相关性较小。16 IRE1 是 UPR 的主调控因子之一,可在 "终端 "ER 应激水平诱导 β 细胞凋亡和退化,而在小鼠模型中抑制 IRE1 可保护 β 细胞,并可能为糖尿病提供治疗机会。此外,抑制另一种 UPR 调节因子,即 eIF2α 激酶 PERK,可逆转受压人类胰岛中存在的翻译阻滞,并预防 NOD 小鼠的糖尿病。值得注意的是,不同的 β 细胞应激之间也存在相互影响,因为在 NOD 小鼠胰岛炎发病前,删除 UPR 基因 ATF6 和 IRE1α,会导致 p21 驱动的早期衰老表型,但矛盾的是,这种表型会减少终末 β 细胞衰老和糖尿病的发病率。未来的研究应探索上述应激信号通路及其前沿基因之间的相互作用,以及它们在不同类型糖尿病中对β细胞功能和存活的综合影响。本评论基于 44 例人类胰岛供体的 scRNA-seq 数据,采用指数评分法,突出了 T1D 和 T2D 中的β细胞应激特征。主要研究结果表明,T1D(T2D 的程度较轻)的特征是炎症应激升高和多种应激信号通路紊乱。在 UPR、细胞凋亡和细胞衰老之间观察到了很强的相关性。 这些结果为Maestas等人先前的体外研究结果6增添了相关的人类疾病信息,并强调了研究自身免疫性或退行性疾病中受影响人体组织的基因特征对于寻找更好、更有针对性的疗法以解决疾病真正复杂程度的相关性。Decio L. Eizirik负责审阅、编辑和添加内容。两位作者都批准了手稿的最终版本。易小燕和Decio L. Eizirik的贡献巨大,符合国际医学期刊编辑委员会的最新准则。易小燕和Decio L. Eizirik为本著作的担保人。作者的研究得到了突破 T1D(前身为国际 JDRF(3-SRA-2022-1201-S-B [1] 和 3-SRA-2022-1201-S-B [2]))、美国国立卫生研究院--人类胰岛研究网络联合体关于 Beta 细胞死亡&amp;从胰腺 β 细胞基因网络到治疗的生存研究网络联盟(HIRN-CBDS)(U01 DK127786 基金);以及美国国立卫生研究院 NIDDK 基金 RO1DK126444 和 RO1DK133881-01。作者声明与本评论无利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Diabetes
Journal of Diabetes ENDOCRINOLOGY & METABOLISM-
CiteScore
6.50
自引率
2.20%
发文量
94
审稿时长
>12 weeks
期刊介绍: Journal of Diabetes (JDB) devotes itself to diabetes research, therapeutics, and education. It aims to involve researchers and practitioners in a dialogue between East and West via all aspects of epidemiology, etiology, pathogenesis, management, complications and prevention of diabetes, including the molecular, biochemical, and physiological aspects of diabetes. The Editorial team is international with a unique mix of Asian and Western participation. The Editors welcome submissions in form of original research articles, images, novel case reports and correspondence, and will solicit reviews, point-counterpoint, commentaries, editorials, news highlights, and educational content.
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