Diabetes最新文献_第7页

Neurodevelopmental Pathways to Obesity and Type 2 Diabetes: Insights From Prenatal Exposure to Maternal Obesity and Gestational Diabetes Mellitus: A Report on Research Supported by Pathway to Stop Diabetes. 肥胖和 2 型糖尿病的神经发育途径：产前暴露于母体肥胖和妊娠糖尿病的启示：杜绝糖尿病之路 "支持的研究报告。

Diabetes Pub Date : 2024-12-01 DOI: 10.2337/dbi24-0012

Kathleen A Page

{"title":"Neurodevelopmental Pathways to Obesity and Type 2 Diabetes: Insights From Prenatal Exposure to Maternal Obesity and Gestational Diabetes Mellitus: A Report on Research Supported by Pathway to Stop Diabetes.","authors":"Kathleen A Page","doi":"10.2337/dbi24-0012","DOIUrl":"10.2337/dbi24-0012","url":null,"abstract":"Incidences of childhood obesity and type 2 diabetes (T2D) are climbing at alarming rates. Evidence points to prenatal exposures to maternal obesity and gestational diabetes mellitus (GDM) as key contributors to these upward trends. Children born to mothers with these conditions face higher risks of obesity and T2D, beyond genetic or shared environmental factors. The underpinnings of this maternal-fetal programming are complex. However, animal studies have shown that such prenatal exposures can lead to changes in brain pathways, particularly in the hypothalamus, leading to obesity and T2D later in life. This article highlights significant findings stemming from research funded by my American Diabetes Association Pathway Accelerator Award and is part of a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. This critical support, received more than a decade ago, paved the way for groundbreaking discoveries, translating the neural programming findings from animal models into human studies and exploring new avenues in maternal-fetal programming. Our BrainChild cohort includes >225 children, one-half of whom were exposed in utero to maternal GDM and one-half born to mothers without GDM. Detailed studies in this cohort, including neuroimaging and metabolic profiling, reveal that early fetal exposure to maternal GDM is linked to alterations in brain regions, including the hypothalamus. These neural changes correlate with increased energy intake and predict greater increases in BMI, indicating that early neural changes may underlie and predict later obesity and T2D, as observed in animal models. Ongoing longitudinal studies in this cohort will provide critical insights toward breaking the vicious cycle of maternal-child obesity and T2D.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1937-1941"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Selective Reduction of Ca2+-Independent Phospholipase A2β (iPLA2β)-Derived Lipid Signaling From Macrophages Mitigates Type 1 Diabetes Development. 选择性减少巨噬细胞的 Ca2+ 依赖性磷脂酶 A2β (iPLA2β) 衍生脂质信号可减轻 1 型糖尿病的发展。

Diabetes Pub Date : 2024-12-01 DOI: 10.2337/db23-0770

Abdulaziz Almutairi, Tayleur D White, Daniel J Stephenson, Benjamin D Stephenson, Ying Gai-Tusing, Paran Goel, Daniel W Phillips, Robert S Welner, Xiaoyong Lei, Bruce D Hammock, Charles E Chalfant, Sasanka Ramanadham

{"title":"Selective Reduction of Ca2+-Independent Phospholipase A2β (iPLA2β)-Derived Lipid Signaling From Macrophages Mitigates Type 1 Diabetes Development.","authors":"Abdulaziz Almutairi, Tayleur D White, Daniel J Stephenson, Benjamin D Stephenson, Ying Gai-Tusing, Paran Goel, Daniel W Phillips, Robert S Welner, Xiaoyong Lei, Bruce D Hammock, Charles E Chalfant, Sasanka Ramanadham","doi":"10.2337/db23-0770","DOIUrl":"10.2337/db23-0770","url":null,"abstract":"Type 1 diabetes (T1D) is a consequence of autoimmune destruction of β-cells, and macrophages (MΦs) have a central role in initiating processes that lead to β-cell demise. We reported that Ca2+-independent phospholipase A2β (iPLA2β)-derived lipid (iDL) signaling contributes to β-cell death. Because MΦs express iPLA2β, we assessed its role in T1D development. We find that selective reduction of myeloid-iPLA2β in spontaneously diabetes-prone NOD mice 1) decreases proinflammatory eicosanoid production by MΦs, 2) favors the anti-inflammatory (M2-like) MΦ phenotype, and 3) diminishes activated CD4+ and CD8+ T-cells phenotype in the pancreatic infiltrate, prior to T1D onset. These outcomes are associated with a significant reduction in T1D. Further, inhibition of select proinflammatory lipid signaling pathways reduces M1-like MΦ polarization and adoptive transfer of M2-like MΦs reduces NOD T1D incidence, suggesting a mechanism by which iDLs impact T1D development. These findings identify MΦ-iPLA2β as a critical contributor to T1D development and potential target to counter T1D onset.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"2022-2033"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of Peptidyl Arginine Deiminase 4-Dependent Macrophage Extracellular Trap Formation in Type 1 Diabetes Pathogenesis. 肽基精氨酸脱氨酶 4 依赖性巨噬细胞胞外陷阱的形成对 1 型糖尿病发病机制的作用

Diabetes Pub Date : 2024-11-01 DOI: 10.2337/db23-1000

Yiming Shen, Ruiya Shi, ShiPing Lu, Yan Wang, Ziqi Zhou, Chenhua Wu, Qi You, Hongye Fan, Jie Wu

引用次数: 0

Leptin Activation of Dorsal Raphe Neurons Inhibits Feeding Behavior. 瘦素激活背侧神经元可抑制摄食行为

Diabetes Pub Date : 2024-11-01 DOI: 10.2337/db24-0207

Nicholas David Maxwell, Cora Erin Smiley, Alia Tereza Sadek, Frances Zoe Loyo-Rosado, Daniel Christian Giles, Victoria Alice Macht, Jennifer Lynn Woodruff, Donzelle Lee Taylor, Victoria Marie Glass, Steven Peter Wilson, Lawrence Patrick Reagan, James Robert Fadel, Claudia Alejandra Grillo

{"title":"Leptin Activation of Dorsal Raphe Neurons Inhibits Feeding Behavior.","authors":"Nicholas David Maxwell, Cora Erin Smiley, Alia Tereza Sadek, Frances Zoe Loyo-Rosado, Daniel Christian Giles, Victoria Alice Macht, Jennifer Lynn Woodruff, Donzelle Lee Taylor, Victoria Marie Glass, Steven Peter Wilson, Lawrence Patrick Reagan, James Robert Fadel, Claudia Alejandra Grillo","doi":"10.2337/db24-0207","DOIUrl":"10.2337/db24-0207","url":null,"abstract":"Leptin is a homeostatic regulatory element that signals the presence of adipocyte energy stores, reduces food intake, and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also controls food intake. Using neuronal tract tracing, pharmacologic and optogenetic approaches, and in vivo microdialysis, combined with behavioral end points, we tested the hypothesis that leptin controls food intake not only by activating hypothalamic leptin receptors (LepRs) but also through activation of LepRs expressed by serotonergic raphe neurons that send projections to the arcuate (ARC). We showed that microinjection of leptin directly into the dorsal raphe nucleus (DRN) reduced food intake in rats. This effect was mediated by LepR-expressing neurons in the DRN, because selective optogenetic activation of these neurons at either their DRN cell bodies or their ARC terminals reduced food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing LepRs that send projections to the ARC. Finally, by using in vivo microdialysis, we showed that leptin administration to the DRN increased 5-HT efflux into the ARC, and specific antagonism of the 5-HT2C receptors in the ARC diminished the leptin anorectic effect. Overall, this study identified a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, identifying a new level of interaction between leptin and serotonin to control food intake. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior and opens alternative routes for the treatment of eating disorders.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1821-1831"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion. 内脏脂肪细胞衍生的细胞外囊泡miR-27a-5p通过抑制胰腺β细胞的胰岛素分泌引起葡萄糖不耐受。

Diabetes Pub Date : 2024-11-01 DOI: 10.2337/db24-0177

Yaqin Zhang, Bin Qian, Yang Yang, Fandi Niu, Changsong Lin, Honglei Yuan, Jianan Wang, Tijun Wu, Yixue Shao, Shulin Shao, Aiming Liu, Jingwen Wu, Peng Sun, Xiaoai Chang, Yan Bi, Wei Tang, Yunxia Zhu, Fang Chen, Dongming Su, Xiao Han

{"title":"Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion.","authors":"Yaqin Zhang, Bin Qian, Yang Yang, Fandi Niu, Changsong Lin, Honglei Yuan, Jianan Wang, Tijun Wu, Yixue Shao, Shulin Shao, Aiming Liu, Jingwen Wu, Peng Sun, Xiaoai Chang, Yan Bi, Wei Tang, Yunxia Zhu, Fang Chen, Dongming Su, Xiao Han","doi":"10.2337/db24-0177","DOIUrl":"10.2337/db24-0177","url":null,"abstract":"Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of miRNAs. However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improved insulin secretion and glucose intolerance in db/db mice. Supporting the function of EV miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs showed their distribution in mouse pancreatic islets. Tracing the injected adeno-associated virus (AAV)-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat resulted in upregulating miR-27a-5p in EVs and serum and elicited mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targeted L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduced insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolished the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EV miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1832-1847"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes: Report of Diabetes Mellitus Interagency Coordinating Committee Workshop. 1 型糖尿病病理生理学、筛查和预防方面不断演变的概念：糖尿病机构间协调委员会研讨会报告》。

Diabetes Pub Date : 2024-11-01 DOI: 10.2337/dbi24-0020

Carla J Greenbaum, Gerald T Nepom, Lauren K Wood-Heickman, Diane K Wherrett, Linda A DiMeglio, Kevan C Herold, Jeffrey P Krischer

{"title":"Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes: Report of Diabetes Mellitus Interagency Coordinating Committee Workshop.","authors":"Carla J Greenbaum, Gerald T Nepom, Lauren K Wood-Heickman, Diane K Wherrett, Linda A DiMeglio, Kevan C Herold, Jeffrey P Krischer","doi":"10.2337/dbi24-0020","DOIUrl":"10.2337/dbi24-0020","url":null,"abstract":"The approval of teplizumab to delay the onset of type 1 diabetes is an important inflection point in the decades-long pursuit to treat the cause of the disease rather than its symptoms. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop of the Diabetes Mellitus Interagency Coordinating Committee titled \"Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes\" to review this accomplishment and identify future goals. Speakers representing Type 1 Diabetes TrialNet (TrialNet) and the Immune Tolerance Network emphasized that the ability to robustly identify individuals destined to develop type 1 diabetes was essential for clinical trials. The presenter from the U.S. Food and Drug Administration described how regulatory approval relied on data from the single clinical trial of TrialNet with testing of teplizumab for delay of clinical diagnosis, along with confirmatory evidence from studies in patients after diagnosis. The workshop reviewed the etiology of type 1 diabetes as a disease involving multiple immune pathways, highlighting the current understanding of prognostic markers and proposing potential strategies to improve the therapeutic response of disease-modifying therapies based on the mechanism of action. While celebrating these achievements funded by the congressionally appropriated Special Diabetes Program, panelists from professional organizations, nonprofit advocacy/funding groups, and industry also identified significant hurdles in translating this research into clinical care.","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1780-1790"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy. PAK3 通过 SREBP1c 在肥胖性心肌病中加剧心脏脂肪毒性

Diabetes Pub Date : 2024-11-01 DOI: 10.2337/db24-0240

Xinyi Chen, Andrea Ruiz-Velasco, Zhiyong Zou, Susanne S Hille, Claire Ross, Oveena Fonseka, Sanskruti R Gare, Nasser Hawimel O Alatawi, Rida Raja, Jiayan Zhang, Namrita Kaur, Xiangjun Zhao, Henrietta Morrell-Davies, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Derk Frank, Martin K Rutter, Christian Pinali, Tao Wang, Tamer M A Mohamed, Oliver J Müller, Wei Liu

{"title":"PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy.","authors":"Xinyi Chen, Andrea Ruiz-Velasco, Zhiyong Zou, Susanne S Hille, Claire Ross, Oveena Fonseka, Sanskruti R Gare, Nasser Hawimel O Alatawi, Rida Raja, Jiayan Zhang, Namrita Kaur, Xiangjun Zhao, Henrietta Morrell-Davies, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Derk Frank, Martin K Rutter, Christian Pinali, Tao Wang, Tamer M A Mohamed, Oliver J Müller, Wei Liu","doi":"10.2337/db24-0240","DOIUrl":"10.2337/db24-0240","url":null,"abstract":"Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating in heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate in cardiomyocytes, and seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated in obese human myocardium, and the murine hearts and cardiomyocytes upon diet- or fatty acid-induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible to the development of cardiac dysfunction upon diet stress, at least partially, because of increased deposition of toxic lipids within the myocardium. Mechanistically, PAK3 promoted the nuclear expression of sterol regulatory element binding protein 1c (SREBP1c) through activation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase β-1 (S6K1) pathway in cardiomyocytes, resulting in abnormal lipid genes profile, accumulation of excessive lipids, and oxidative stress. More importantly, PAK3 knockdown attenuated fatty acid-induced lipotoxicity and cell death in rat and human cardiomyocytes. More importantly, the S6K1 or SREBP1c inhibitor alleviated PAK3-triggered intracellular lipid overload and cardiac dysfunction under obese stress. Collectively, we have demonstrated that PAK3 impairs myocardial lipid homeostasis, while inhibition of cardiac lipotoxicity mitigates cardiac dysfunction. Our study provides a promising therapeutic strategy for ameliorating obesity cardiomyopathy.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1805-1820"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pancreatic β-Cell TRAPδ Deficiency Reduces Insulin Production but Improves Insulin Sensitivity. 胰腺β细胞TRAPδ缺乏会减少胰岛素分泌，但会提高胰岛素敏感性。

Diabetes Pub Date : 2024-11-01 DOI: 10.2337/db23-0984

Jiyun Guo, Yanshu Yang, Ning Xu, Xin Li, Ying Yang, Wenli Feng, Yuanyuan Ye, Xiaoxi Xu, Jingqiu Cui, Ming Liu, Yumeng Huang

{"title":"Pancreatic β-Cell TRAPδ Deficiency Reduces Insulin Production but Improves Insulin Sensitivity.","authors":"Jiyun Guo, Yanshu Yang, Ning Xu, Xin Li, Ying Yang, Wenli Feng, Yuanyuan Ye, Xiaoxi Xu, Jingqiu Cui, Ming Liu, Yumeng Huang","doi":"10.2337/db23-0984","DOIUrl":"10.2337/db23-0984","url":null,"abstract":"The translocon-associated protein-δ (TRAPδ) plays a role in insulin biosynthesis within pancreatic β-cells. However, its pathophysiological significance in maintaining islet β-cell function and glucose homeostasis remains unclear. In this study, we generated a mouse model featuring pancreatic β-cell-specific deletion of TRAPδ (TRAPδ βKO). Our findings revealed that TRAPδ βKO resulted in decreased circulating insulin levels in mice fed either a normal chow diet or a high-fat diet. Multiple independent experiments established that although TRAPδ deletion reduced insulin content in the islets, it had no discernible effect on insulin gene expression, the insulin to proinsulin ratio, or the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a pivotal role in the transcription of the insulin gene or proinsulin processing. However, untranslocated preproinsulin levels were significantly increased when islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency may hinder preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Remarkably, despite the moderate decrease in circulating insulin levels in TRAPδ βKO mice, their glucose levels remained unaffected, indicating the presence of compensatory mechanisms that help maintain glucose homeostasis. Insulin tolerance tests further revealed improved insulin sensitivity, accompanied by upregulation of phosphorylated AKT in the peripheral tissues of TRAPδ βKO mice. Collectively, these data highlight the important role of TRAPδ in insulin biosynthesis and β-cell function. The moderate reduction in circulating insulin appears to promote insulin sensitivity in insulin target tissues.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1848-1861"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Association Between Low Sex Hormone-Binding Globulin and Increased Risk of Type 2 Diabetes Is Mediated by Increased Visceral and Liver Fat: Results From Observational and Mendelian Randomization Analyses. 性激素结合球蛋白低与 2 型糖尿病风险增加之间的关联是由内脏和肝脏脂肪增加介导的：观察性分析和孟德尔随机分析的结果。

Diabetes Pub Date : 2024-11-01 DOI: 10.2337/db23-0982

Theresa A Stangl, Chantal M Wiepjes, Roelof A J Smit, Astrid van Hylckama Vlieg, Hildo J Lamb, Jeroen H P M van der Velde, Esther Winters-van Eekelen, Sebastiaan C Boone, Martijn C G J Brouwers, Frits R Rosendaal, Martin den Heijer, Annemieke C Heijboer, Renée de Mutsert

{"title":"Association Between Low Sex Hormone-Binding Globulin and Increased Risk of Type 2 Diabetes Is Mediated by Increased Visceral and Liver Fat: Results From Observational and Mendelian Randomization Analyses.","authors":"Theresa A Stangl, Chantal M Wiepjes, Roelof A J Smit, Astrid van Hylckama Vlieg, Hildo J Lamb, Jeroen H P M van der Velde, Esther Winters-van Eekelen, Sebastiaan C Boone, Martijn C G J Brouwers, Frits R Rosendaal, Martin den Heijer, Annemieke C Heijboer, Renée de Mutsert","doi":"10.2337/db23-0982","DOIUrl":"10.2337/db23-0982","url":null,"abstract":"The aim of this study was to investigate the associations among sex hormone-binding globulin (SHBG), visceral adipose tissue (VAT), liver fat content, and risk of type 2 diabetes (T2D). In the Netherlands Epidemiology of Obesity study, 5,690 women (53%) and men (47%) without preexisting diabetes were included and followed for incident T2D. SHBG concentrations were measured in all participants, VAT was measured using MRI, and liver fat content was measured using proton magnetic resonance spectroscopy in a random subset of 1,822 participants. We examined associations between SHBG and liver fat using linear regression and bidirectional Mendelian randomization analyses and between SHBG and T2D using Cox regression adjusted for confounding and additionally for VAT and liver fat to examine mediation. Mean age was 56 (SD 6) years, mean BMI was 30 (SD 4) kg/m2, median SHBG was 47 (interquartile range [IQR] 34-65) nmol/L in women and 34 (26-43) nmol/L in men, and median liver fat was 3.4% (IQR 1.6-8.2%) in women and 6.0% (2.9-13.5%) in men. Compared with the highest SHBG quartile, liver fat was 2.9-fold (95% CI 2.4, 3.4) increased in women and 1.6-fold (95% CI 1.3, 1.8) increased in men, and the hazard ratio of T2D was 4.9 (95% CI 2.4, 9.9) in women and 1.8 (1.1, 2.9) in men. Genetically predicted SHBG was associated with liver fat content (women: SD -0.45 [95% CI -0.55, -0.35]; men: natural logarithm, -0.25 [95% CI -0.34, -0.16]). VAT and liver fat together mediated 43% (women) and 60% (men) of the SHBG-T2D association. To conclude, in a middle-aged population with overweight, the association between low SHBG and increased risk of T2D was, for a large part, mediated by increased VAT and liver fat.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1793-1804"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Müller Cells Harboring Exosomal lncRNA OGRU Modulate Microglia Polarization in Diabetic Retinopathy by Serving as miRNA Sponges. 携带外泌体lncRNA OGRU的Müller细胞通过充当miRNA海绵调节糖尿病视网膜病变中的小胶质细胞极化。

Diabetes Pub Date : 2024-11-01 DOI: 10.2337/db23-1015

ShuHua Fu, WenJing Sun, Lu Liu, JiPing Xiao, Jian Xiong, YaoYun Hu, QianQian Zhou, XiaoLong Yin

{"title":"Müller Cells Harboring Exosomal lncRNA OGRU Modulate Microglia Polarization in Diabetic Retinopathy by Serving as miRNA Sponges.","authors":"ShuHua Fu, WenJing Sun, Lu Liu, JiPing Xiao, Jian Xiong, YaoYun Hu, QianQian Zhou, XiaoLong Yin","doi":"10.2337/db23-1015","DOIUrl":"10.2337/db23-1015","url":null,"abstract":"Diabetic retinopathy (DR) is one of the most common complications of diabetes worldwide and is associated with visual loss and blindness. However, effective treatments for both early- and late-stage DR remain lacking. A streptozotocin-induced diabetic mouse model and high glucose (HG)-treated Müller cell model were established. M1/M2 microglia polarization was assessed by immunofluorescence staining and flow cytometry. Expression of long noncoding RNA (lncRNA) OGRU, cytokines, and other key molecules was detected by quantitative RT-PCR or Western blot. ELISA was used to monitor cytokine secretion. Müller cell-derived exosomes were isolated and characterized by nanopartical tracking analysis, Western blot, and transmission electron microscopy, and exosome uptake assay was used to monitor the intercellular transport of exosomes. Associations among lncRNA-miRNA-mRNA networks were validated by RNA pulldown and RNA immunoprecipitation and dual luciferase assays. Increased M1 polarization but decreased M2 polarization of retinal microglia was observed in DR mice. HG-treated Müller cell-derived exosomes transported OGRU into microglia and promoted microglia polarization toward the M1 phenotype. Mechanistically, OGRU served as a competing endogenous RNA for miR-320-3p, miR-221-3p, and miR-574-5p to regulate aldose reductase (AR), PFKFB3, and glucose transporter 1 (GLUT1) expression in microglia, respectively. Loss of miR-320-3p/miR-221-3p/miR-574-5p or reinforced AR/PFKFB3/GLUT1 abrogated OGRU silencing-mediated microglia polarization in vitro. In vivo studies further showed that OGRU/miR-320-3p/AR, OGRU/miR-221-3p/PFKFB3, and OGRU/miR-574-5p/GLUT1 axes regulated microglia polarization in DR mice. Collectively, Müller cell-derived exosomal OGRU regulated microglia polarization in DR by modulating OGRU/miR-320-3p/AR, OGRU/miR-221-3p/PFKFB3, and OGRU/miR-574-5p/GLUT1 axes.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1919-1934"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0