IF 7.7 1区医学

Diabetes Pub Date : 2024-11-19 DOI: 10.2337/db24-0756

Samantha Mar, Ekaterina Filatov, Shugo Sasaki, Majid Mojibian, Dahai Zhang, Angela Yang, Cuilan Nian, Francis C. Lynn

{"title":"Tracking insulin- and glucagon-expressing cells in vitro and in vivo using a double reporter human embryonic stem cell line","authors":"Samantha Mar, Ekaterina Filatov, Shugo Sasaki, Majid Mojibian, Dahai Zhang, Angela Yang, Cuilan Nian, Francis C. Lynn","doi":"10.2337/db24-0756","DOIUrl":"https://doi.org/10.2337/db24-0756","url":null,"abstract":"Human embryonic stem cell (hESC)-derived pancreatic alpha and beta cells can be used to develop cell replacement therapies to treat diabetes. However, recent published differentiation protocols yield varying amounts of alpha and beta cells amidst heterogeneous cell populations. To visualize and isolate hESC-derived alpha and beta cells, we generated a GLUCAGON-2AmScarlet and INSULIN-2A-EGFP dual fluorescent reporter (INSEGFPGCGmScarlet) hESC line using CRISPR/Cas9. We established robust expression of EGFP and mScarlet fluorescent proteins in insulin- and glucagon-expressing cells respectively without compromising the differentiation or function of these cells. We also showed the insulin- and glucagon-expressing bihormonal population at the maturing endocrine cell stage (Stage 6) of our pancreatic islet differentiation lose insulin expression over time, while maintaining an alpha-like expression profile, suggesting these bihormonal cells are cell autonomously fated to become alpha-like cells. We also demonstrated this cell line can be used to monitor hESC-derived insulin- and glucagonexpressing cells, and hESC-derived islet morphology in vivo by transplanting them into the anterior chamber of the eye in mice. Together, the INSEGFPGCGmScarlet hESC line provides an efficient strategy for tracking populations of hESC-derived beta- and alpha-like cells.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of the HPA axis does not explain non-responsiveness to GLP-1R agonist treatment in individuals with type 2 diabetes 激活 HPA 轴不能解释 2 型糖尿病患者对 GLP-1R 激动剂治疗无反应的原因

IF 7.7 1区医学

Diabetes Pub Date : 2024-11-19 DOI: 10.2337/db24-0463

Sevilay Tokgöz, Marti Boss, Theodorus JP Jansen, Rick Meijer, Cathelijne Frielink, Arianne C van Bon, Cees J Tack, Bastiaan E de Galan, Martin Gotthardt

{"title":"Activation of the HPA axis does not explain non-responsiveness to GLP-1R agonist treatment in individuals with type 2 diabetes","authors":"Sevilay Tokgöz, Marti Boss, Theodorus JP Jansen, Rick Meijer, Cathelijne Frielink, Arianne C van Bon, Cees J Tack, Bastiaan E de Galan, Martin Gotthardt","doi":"10.2337/db24-0463","DOIUrl":"https://doi.org/10.2337/db24-0463","url":null,"abstract":"Glucagon-like peptide 1 receptor (GLP-1R) agonists fail to reduce weight and improve glucose control in a sizable minority of people with type 2 diabetes. We hypothesized that stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by GLP-1R agonists, thus inducing cortisol secretion, could explain this unresponsiveness to GLP-1R agonists. To assess the effects of GLP-1R agonist treatment on the HPA axis, we selected ten individuals with type 2 diabetes with (5 women/5 men) and nine without (4 women/5 men) an adequate response to GLP-1R agonists and used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography (PET)/computed tomography (CT) to quantify GLP-1R expression in the pituitary. Oral glucose tolerance and 24 h urinary cortisol excretion was measured in all participants. Pituitary tracer uptake was observed in all participants with no significant difference between responders and non-responders. Pituitary tracer uptake correlated with the area under the curve for ACTH, urinary cortisol to creatinine ratio and age. Interestingly, men had higher pituitary tracer uptake than women. In conclusion, this study does not indicate a role for pituitary GLP-1R expression and HPA axis stimulation to explain the difference in treatment response to GLP-1R agonists among individuals with type 2 diabetes. The findings of substantial pituitary GLP-1R expression and the significant sex differences require further research.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"8 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteomic Signature of Body Mass Index and Risk of Type 2 Diabetes 体重指数与 2 型糖尿病风险的蛋白质组特征

IF 7.7 1区医学

Diabetes Pub Date : 2024-11-19 DOI: 10.2337/db24-0329

Xuan Wang, Hao Ma, Minghao Kou, Yoriko Heianza, Vivian Fonseca, Lu Qi

{"title":"Proteomic Signature of Body Mass Index and Risk of Type 2 Diabetes","authors":"Xuan Wang, Hao Ma, Minghao Kou, Yoriko Heianza, Vivian Fonseca, Lu Qi","doi":"10.2337/db24-0329","DOIUrl":"https://doi.org/10.2337/db24-0329","url":null,"abstract":"The obesity diagnosis by body mass index (BMI) exhibits considerable interindividual heterogeneity in metabolic phenotypes and risk of developing type 2 diabetes (T2D). We investigated the association of proteomic signature of BMI and T2D and examined whether the proteomic signature of BMI improves prediction of T2D risk. This study included 41,427 adults in the UK Biobank who were free of T2D at baseline and had complete data on proteomics metrics assessed by antibody based Olink assay. The main exposure was a proteomic BMI score (pro-BMI score) calculated from 67 pre-identified plasma proteins associated with BMI. During a median follow-up of 13.7 years, 2,030 incident events of T2D were documented. We observed that a higher proteomic BMI (pro-BMI) score was significantly associated with a higher risk of T2D independent of actual BMI, waist-to-hip ratio, and polygenic risk score for BMI (hazard ratio (HR) comparing the highest with the lowest quartiles was 3.81, 95% CI, 3.08 – 4.71). Pro- BMI score significantly increased the C index when added to a reference model with age, sex, and BMI (C index change, 0.023 [95%CI, 0.018 to 0.027]). Proteomic signature of BMI is significantly associated with the risk of T2D independent of BMI, WHR and genetic susceptibility to obesity. When added to actual BMI, the proteomic signature of BMI provides significant but modest improvement in discrimination.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"46 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts. 心血管自主神经病变与 1 型和 2 型糖尿病患者肾功能衰退的风险：PERL 和 ACCORD 队列的研究结果。

IF 7.7 1区医学

Diabetes Pub Date : 2024-05-01 DOI: 10.2337/db23-0247

Yaling Tang, Lynn Ang, Mamta Jaiswal, Brendan R Dillon, Nazanene H Esfandiari, Hetal S Shah, Cathie Spino, Cindy Plunkett, Bruce A Perkins, Rodica Pop-Busui, Alessandro Doria

{"title":"Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts.","authors":"Yaling Tang, Lynn Ang, Mamta Jaiswal, Brendan R Dillon, Nazanene H Esfandiari, Hetal S Shah, Cathie Spino, Cindy Plunkett, Bruce A Perkins, Rodica Pop-Busui, Alessandro Doria","doi":"10.2337/db23-0247","DOIUrl":"10.2337/db23-0247","url":null,"abstract":"Results of previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among people with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N = 469) and with type 2 diabetes (T2D) from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (N = 7,973). Baseline CAN was ascertained with electrocardiogram-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss of ≥5 mL/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed-effects, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 mL/min/1.73 m2/year (95% CI -1.93 to -0.37; P = 4.0 × 10-3) in PERL and 0.34 mL/min/1.73 m2/year (95% CI -0.49 to -0.19; P = 6.3 × 10-6) in ACCORD. This translated to 2.11 (95% CI 1.23-3.63; P = 6.9 × 10-3) and 1.39 (95% CI 1.20-1.61; P = 1.1 × 10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (hazard ratio 2.60 [95% CI 1.15-5.45], P = 0.02, in PERL and hazard ratio 1.54 [95% CI 1.28-1.84], P = 3.8 × 10-6, in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help with development of new therapies to prevent kidney function decline in patients with diabetes.Article highlights: ","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":" ","pages":"751-762"},"PeriodicalIF":7.7,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9892156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human Genetic Variation at rs10071329 Correlates with Adiposity-related Traits, Modulates PPARGC1B Expression, and Alters Brown Adipocyte Function rs10071329 的人类遗传变异与脂肪相关特征有关，可调节 PPARGC1B 的表达并改变棕色脂肪细胞的功能

IF 7.7 1区医学

Diabetes Pub Date : 2024-01-08 DOI: 10.2337/db23-0531

Mi Huang, Rashmi B. Prasad, Daniel E. Coral, Line Hjort, Daniel T. R. Minja, Hindrik Mulder, Paul W. Franks, Sebastian Kalamajski

{"title":"Human Genetic Variation at rs10071329 Correlates with Adiposity-related Traits, Modulates PPARGC1B Expression, and Alters Brown Adipocyte Function","authors":"Mi Huang, Rashmi B. Prasad, Daniel E. Coral, Line Hjort, Daniel T. R. Minja, Hindrik Mulder, Paul W. Franks, Sebastian Kalamajski","doi":"10.2337/db23-0531","DOIUrl":"https://doi.org/10.2337/db23-0531","url":null,"abstract":"Human genetic variation in PPARGC1B has been associated with adiposity, but the genetic variants that affect PPARGC1B expression have not been experimentally determined. Here, guided by previous observational data, we used CRISPR/Cas9 to scarlessly edit the alleles of the candidate causal genetic variant rs10071329 in a human brown adipocyte cell line (hBAs). Switching the rs10071329 genotype from A/A to G/G enhanced PPARGC1B expression throughout the adipogenic differentiation, identifying rs10071329 as a cis-eQTL. The higher PPARGC1B expression in G/G cells coincided with greater accumulation of triglycerides, and higher expression of mitochondria-encoded genes, but without significant effects on adipogenic marker expression. Furthermore, G/G cells had improved basal- and norepinephrine-stimulated mitochondrial respiration, possibly relating to enhanced mitochondrial gene expression. The G/G cells also exhibited increased norepinephrine-stimulated glycerol release, indicating improved lipolysis. Altogether, our results showed that rs10071329 is a cis-eQTL, with the G/G genotype conferring enhanced PPARGC1B expression, with consequent improved mitochondrial function and response to norepinephrine in brown adipocytes. This genetic variant, and as yet undetermined eQTLs, at PPARGC1B could prove useful in genotype-based precision medicine for obesity treatment.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"215 1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139400508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bridging the Gap: Pancreas Tissue Slices From Organ and Tissue Donors for the Study of Diabetes Pathogenesis 缩小差距：利用器官和组织捐献者的胰腺组织切片研究糖尿病发病机制

IF 7.7 1区医学

Diabetes Pub Date : 2023-12-20 DOI: 10.2337/dbi20-0018

Christian M. Cohrs, Chunguang Chen, Mark A. Atkinson, Denise M. Drotar, Stephan Speier

{"title":"Bridging the Gap: Pancreas Tissue Slices From Organ and Tissue Donors for the Study of Diabetes Pathogenesis","authors":"Christian M. Cohrs, Chunguang Chen, Mark A. Atkinson, Denise M. Drotar, Stephan Speier","doi":"10.2337/dbi20-0018","DOIUrl":"https://doi.org/10.2337/dbi20-0018","url":null,"abstract":"Over the last two decades, increased availability of human pancreatic tissues has allowed for major expansions in our understanding of islet biology in health and disease. Indeed, studies of fixed and frozen pancreatic tissues, as well as efforts using viable isolated islets obtained from organ donors, have provided significant insights toward our understanding of diabetes. However, the procedures associated with islet isolation result in distressed cells that have been removed from any surrounding influence. The pancreas tissue slice technology was developed as an in situ approach to overcome certain limitations associated with studies on isolated islets or fixed tissue. In this Perspective, we discuss the value of this novel platform and review how pancreas tissue slices, within a short time, have been integrated in numerous studies of rodent and human islet research. We show that pancreas tissue slices allow for investigations in a less perturbed organ tissue environment, ranging from cellular processes, over peri-islet modulations, to tissue interactions. Finally, we discuss the considerations and limitations of this technology in its future applications. We believe the pancreas tissue slices will help bridge the gap between studies on isolated islets and cells to the systemic conditions by providing new insight into physiological and pathophysiological processes at the organ level. Article Highlights Human pancreas tissue slices represent a novel platform to study human islet biology in close to physiological conditions. Complementary to established technologies, such as isolated islets, single cells, and histological sections, pancreas tissue slices help bridge our understanding of islet physiology and pathophysiology from single cell to intact organ. Diverse sources of viable human pancreas tissue, each with distinct characteristics to be considered, are available to use in tissue slices for the study of diabetes pathogenesis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"307 3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138822890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multi-omics analyses with stool-type stratification in patient cohorts and Blautia identification as a potential bacterial modulator in T2DM 多组学分析与患者队列中的粪便类型分层以及将 Blautia 鉴定为 T2DM 潜在的细菌调节剂

IF 7.7 1区医学

Diabetes Pub Date : 2023-12-11 DOI: 10.2337/db23-0447

Qian Guo, Zezheng Gao, Linhua Zhao, Han Wang, Zhen Luo, Doris Vandeputte, Lisha He, Mo Li, Sha Di, Yanwen Liu, Jiaheng Hou, Xiaoqing Jiang, Huaiqiu Zhu, Xiaolin Tong

{"title":"Multi-omics analyses with stool-type stratification in patient cohorts and Blautia identification as a potential bacterial modulator in T2DM","authors":"Qian Guo, Zezheng Gao, Linhua Zhao, Han Wang, Zhen Luo, Doris Vandeputte, Lisha He, Mo Li, Sha Di, Yanwen Liu, Jiaheng Hou, Xiaoqing Jiang, Huaiqiu Zhu, Xiaolin Tong","doi":"10.2337/db23-0447","DOIUrl":"https://doi.org/10.2337/db23-0447","url":null,"abstract":"Heterogeneity in host and gut microbiota hampers microbial precision intervention of type 2 diabetes mellitus (T2DM). Here, we investigate novel features for patient-stratification and bacterial modulators for intervention, using cross-sectional patient cohorts and animal experiments. We collected stool/blood/urine samples from 103 recent-onset T2DM patients and 25 healthy controls (HCs), performed gut microbial composition/metabolite profiling, and combined it with host-transcriptome/metabolome/cytokines and clinical data. Stool-type (dry/loose-stool), a feature of stool-microenvironment recently explored in microbiome studies, was used for T2DM patientstratification as it explained most of the variation in multi-omics dataset among all clinical parameters in our covariate analysis. T2DM with dry-stool (DM-DS) and loose-stool (DM-LS) were clearly differentiated from HC and each other by LightGBM-models, optimal among multiple machine-learning models. Compared to DM-DS, DM-LS exhibited discordant gut microbial taxonomic and functional profiles, severe host metabolic disorder, and excessive insulin secretion. Further cross-measurement-association-analysis linked the differential microbial profiles, in particular Blautia abundances, to T2DM phenotypes in our stratified multi-omics dataset. Notably, oral supplementation of Blautia to T2DM mice induced inhibitory effects on lipid accumulation, weight gain, and blood-glucose elevation with simultaneous modulation of gut bacterial composition, revealing the therapeutic potential of Blautia. Our study highlights the clinical implications of stool-microenvironment stratification and Blautia supplementation in T2DM, offering promising prospects for microbial precision treatment of metabolic diseases.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"9 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138571369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acute activation of GFRAL in the area postrema contributes to glucose regulation independent of weight. 后膜区 GFRAL 的急性激活有助于葡萄糖调节，与体重无关。

IF 7.7 1区医学

Diabetes Pub Date : 2023-12-08 DOI: 10.2337/db23-0705

Song-Yang Zhang, Zahra Danaei, Kyla Bruce, Jennifer F.M. Chiu, Tony K.T. Lam

引用次数: 0

Overexpression of UBE2E2 in mouse pancreatic β-cells leads to glucose intolerance via reduction of the β-cell mass 在小鼠胰腺β细胞中过表达 UBE2E2 可通过减少β细胞质量导致葡萄糖不耐受症

IF 7.7 1区医学

Diabetes Pub Date : 2023-12-08 DOI: 10.2337/db23-0150

Yoshitaka Sakurai, Naoto Kubota, Iseki Takamoto, Nobuhiro Wada, Masakazu Aihara, Takanori Hayashi, Tetsuya Kubota, Yuta Hiraike, Takayoshi Sasako, Harumi Nakao, Atsu Aiba, Yoko Chikaoka, Takeshi Kawamura, Takashi Kadowaki, Toshimasa Yamauchi

{"title":"Overexpression of UBE2E2 in mouse pancreatic β-cells leads to glucose intolerance via reduction of the β-cell mass","authors":"Yoshitaka Sakurai, Naoto Kubota, Iseki Takamoto, Nobuhiro Wada, Masakazu Aihara, Takanori Hayashi, Tetsuya Kubota, Yuta Hiraike, Takayoshi Sasako, Harumi Nakao, Atsu Aiba, Yoko Chikaoka, Takeshi Kawamura, Takashi Kadowaki, Toshimasa Yamauchi","doi":"10.2337/db23-0150","DOIUrl":"https://doi.org/10.2337/db23-0150","url":null,"abstract":"Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes (E2s) involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Herein, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in non-coding regions was associated with upregulation of the UBE2E2 mRNA in the human pancreas. While glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic β-cells-specific Ube2e2-transgenic (TG) mice exhibited reduced insulin secretion and decreased β-cell mass. In the TG mice, suppressed proliferation of β-cells before the weaning period and under the high-fat-diet condition was accompanied by elevated gene expression levels of p21, resulting in decreased postnatal β-cell mass expansion and compensatory β-cell hyperplasia, respectively. In the TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin-protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in the β-cells play an important role in regulating glucose homeostasis and β-cell mass.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"22 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138559149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RFX6 maintains gene expression and function of adult human islet α cells RFX6 可维持成人胰岛 α 细胞的基因表达和功能

IF 7.7 1区医学

Diabetes Pub Date : 2023-12-08 DOI: 10.2337/db23-0483

Vy M. N. Coykendall, Mollie F. Qian, Krissie Tellez, Austin Bautista, Romina J. Bevacqua, Xueying Gu, Yan Hang, Martin Neukam, Weichen Zhao, Charles Chang, Patrick E. MacDonald, Seung K. Kim

{"title":"RFX6 maintains gene expression and function of adult human islet α cells","authors":"Vy M. N. Coykendall, Mollie F. Qian, Krissie Tellez, Austin Bautista, Romina J. Bevacqua, Xueying Gu, Yan Hang, Martin Neukam, Weichen Zhao, Charles Chang, Patrick E. MacDonald, Seung K. Kim","doi":"10.2337/db23-0483","DOIUrl":"https://doi.org/10.2337/db23-0483","url":null,"abstract":"Mutations in the gene encoding the transcription factor RFX6 are associated with human diabetes mellitus. Within pancreatic islets, RFX6 expression is most abundant in islet α cells, and α cell RFX6 expression is altered in diabetes. However, the roles of RFX6 in regulating gene expression, glucagon output and other crucial human adult α cell functions are not yet understood. We developed a method for selective genetic targeting of human α cells and assessed RFX6-dependent α cell function. RFX6 suppression with RNA interference led to impaired α cell exocytosis and dysregulated glucagon secretion in vitro and in vivo. By contrast, these phenotypes were not observed with RFX6 suppression across all islet cells. Transcriptomics in α cells revealed RFX6-dependent expression of genes governing nutrient sensing, hormone processing, and secretion, with some of these exclusively expressed in human α cells. Mapping of RFX6 DNA-binding sites in primary human islet cells identified a subset of direct RFX6 target genes. Together, these data unveil RFX6-dependent genetic targets and mechanisms crucial for regulating adult human α cell function.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"109 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138559315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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