Hypoadiponectinemia and Gestational Diabetes
低脂联素血症和妊娠期糖尿病
基本信息
- 批准号:10753827
- 负责人:
- 金额:$ 48.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdipocytesAdverse effectsAgonistAlpha CellAttenuatedBeta CellBloodCell ProliferationCellsCirculationCommunicationCultured CellsDataDefectEndocrineFailureFatty acid glycerol estersFirst Pregnancy TrimesterFunctional disorderFundingGene ExpressionGenesGeneticGestational DiabetesGlucagonGlucoseHealthHormone secretionHumanHyperglycemiaIn VitroInsulinInsulin ResistanceIslet CellKnock-outMediatingMetabolicMetabolic stressMetabolismMicroRNAsMusObesityObesity EpidemicOrganPancreasPathologicPathway interactionsPlacentaPlacental LactogenPostpartum PeriodPregnancyPregnancy OutcomePrevalenceProductionReportingResearchRisk FactorsRoleSecond Pregnancy TrimesterStructure of alpha Cell of isletTissuesadiponectinconditional knockoutdesignextracellular vesiclesglucagon-like peptide 1glucose metabolismglucose toleranceimprovedinsulin secretionisletknockout genelipid metabolismmiRNA expression profilingmouse modeloffspringparacrinepregnantreceptorsuccess
项目摘要
SUMMARY
Obesity is a key risk factor for Gestational diabetes mellitus (GDM). Due to the obesity epidemic, the
prevalence of GDM has reached an alarming level. Most importantly, GDM has many adverse effects on
pregnancy outcomes and postpartum maternal and offspring health. Therefore, it is urgent to elucidate the
pathological mechanisms of GDM. Adiponectin is an adipocyte-secreted hormone that improves glucose and
lipid metabolism. Hypoadiponectinemia before pregnancy and during the first and second trimesters strongly
predicts GDM. Our studies from the previous funding period have demonstrated that adiponectin deficiency
causes hyperglycemia and other metabolic abnormalities in pregnant mice. Interestingly, our studies revealed
that adiponectin controls maternal metabolic adaptation by indirectly increasing β-cell proliferation and insulin
production via placental lactogen (PL). However, decreased insulin secretion rates were still observed in size-
matched islets from adiponectin gene knockout (Adipoq-/-) dams indicating additional mechanisms are involved
besides β-cell proliferation. Extracellular vesicles (EVs) are well-conserved for intercellular and intra-organ
communication. Pregnancy robustly increases EV levels in maternal circulation, partially attributed to placental-
derived small EVs (psEVs). Consistent with other reports, our preliminary studies observed a stimulative effect
of adiponectin on psEVs production. Importantly, psEVs enhanced glucose-induced insulin secretion of
cultured islets. These data suggest that adiponectin, psEVs, and PL provide a pathway for fat/placenta/islet
intra-organ crosstalk. During the last funding period, our study also identified a crucial role of pancreatic α-cells
in maternal metabolic adaptation. Our study demonstrated that pregnancy increases glucagon-like peptide-1
(GLP-1) production from α-cells and then enhances maternal insulin secretion. A significant reduction of
pancreatic GLP-1 was detected in Adipoq-/- dams. Notably, conditionally knocking out the adiponectin receptor
1 (AdipoR1) gene in α-cells significantly reduced GLP-1 production and glucose tolerance during pregnancy.
Therefore, we hypothesize that adiponectin regulates islet adaptation to pregnancy through both
fat/placenta/islet intra-organ crosstalk and intraislet paracrine. We will use genetic mouse models and human
placenta and islets to 1) define the role of psEVs in adiponectin-regulated islet adaptation to pregnancy; 2)
determine how adiponectin augments maternal insulin production through α-cells. The anticipated success of
this project will have a significant impact on the research of maternal metabolic adaptation.
总结
肥胖是妊娠期糖尿病(GDM)的一个重要危险因素。由于肥胖症的流行,
GDM的发病率已经达到了令人担忧的水平。最重要的是,GDM有许多不利影响,
妊娠结局和产后母婴健康。因此,迫切需要澄清
GDM的病理机制脂联素是一种脂肪细胞分泌的激素,可改善血糖,
脂质代谢孕前、孕早期和孕中期的低脂联素血症严重
GDM预测。我们在上一个资助期的研究表明,脂联素缺乏症
导致怀孕小鼠的高血糖和其他代谢异常。有趣的是,我们的研究显示,
脂联素通过间接增加β细胞增殖和胰岛素来控制母体代谢适应,
通过胎盘催乳素(PL)产生。然而,在尺寸上仍然观察到胰岛素分泌率降低-
来自脂联素基因敲除(Adipoq-/-)母鼠的匹配胰岛表明涉及其他机制
除了β细胞增殖。细胞外囊泡(EV)在细胞间和器官内是非常保守的
通信妊娠强烈增加母体循环中的EV水平,部分归因于胎盘-
衍生的小EV(psEV)。与其他报告一致,我们的初步研究观察到了刺激效应
脂联素对psEVs产生的影响。重要的是,psEV增强了葡萄糖诱导的胰岛素分泌,
培养的胰岛。这些数据表明,脂联素、psEV和PL为脂肪/胎盘/胰岛提供了一个途径,
器官内串扰在上一个资助期间,我们的研究还确定了胰腺α细胞的关键作用,
在母体代谢适应方面。我们的研究表明,怀孕增加胰高血糖素样肽-1
(GLP-1)的产生,然后增强母体胰岛素分泌。的显著减少
在Adipoq-/-母鼠中检测到胰腺GLP-1。值得注意的是,有条件地敲除脂联素受体
1(AdipoR 1)基因显著降低妊娠期间GLP-1的产生和葡萄糖耐量。
因此,我们假设脂联素通过这两种途径调节胰岛对妊娠的适应,
脂肪/胎盘/胰岛器官内串扰和胰岛内旁分泌。我们将使用遗传小鼠模型和人类
胎盘和胰岛1)确定psEV在脂联素调节的胰岛适应妊娠中的作用; 2)
确定脂联素如何通过α细胞增加母体胰岛素的产生。预期的成功
该项目将对母体代谢适应的研究产生重要影响。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Adiponectin Promotes Maternal β-Cell Expansion Through Placental Lactogen Expression.
脂联素通过胎盘泌乳原表达促进母体β细胞扩增。
- DOI:10.2337/db20-0471
- 发表时间:2021
- 期刊:
- 影响因子:7.7
- 作者:Qiao,Liping;Saget,Sarah;Lu,Cindy;HayJr,WilliamW;Karsenty,Gerard;Shao,Jianhua
- 通讯作者:Shao,Jianhua
High-fat feeding reprograms maternal energy metabolism and induces long-term postpartum obesity in mice.
高脂肪喂养会重新编程母体能量代谢并诱导小鼠长期产后肥胖。
- DOI:10.1038/s41366-018-0304-x
- 发表时间:2019
- 期刊:
- 影响因子:0
- 作者:Qiao,Liping;Chu,Kayee;Wattez,Jean-Sebastien;Lee,Samuel;Gao,Hongfei;Feng,Gen-Sheng;HayJr,WilliamW;Shao,Jianhua
- 通讯作者:Shao,Jianhua
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Jianhua Shao其他文献
Jianhua Shao的其他文献
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{{ truncateString('Jianhua Shao', 18)}}的其他基金
Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production
α细胞来源的细胞外囊泡和母体胰岛素的产生
- 批准号:
10681939 - 财政年份:2023
- 资助金额:
$ 48.62万 - 项目类别:
Pancreatic alpha-cells and Maternal metabolic Adaptation
胰腺α细胞和母体代谢适应
- 批准号:
10681909 - 财政年份:2023
- 资助金额:
$ 48.62万 - 项目类别:
Brown adipose tissue development and fetal growth
棕色脂肪组织发育和胎儿生长
- 批准号:
10539636 - 财政年份:2022
- 资助金额:
$ 48.62万 - 项目类别:
Brown adipose tissue development and fetal growth
棕色脂肪组织发育和胎儿生长
- 批准号:
10687215 - 财政年份:2022
- 资助金额:
$ 48.62万 - 项目类别:
The maternal-fetal adiponectin differential and fetal fat deposition
母胎脂联素差异和胎儿脂肪沉积
- 批准号:
8900277 - 财政年份:2012
- 资助金额:
$ 48.62万 - 项目类别:
The maternal-fetal adiponectin differential and fetal fat deposition
母胎脂联素差异和胎儿脂肪沉积
- 批准号:
8708063 - 财政年份:2012
- 资助金额:
$ 48.62万 - 项目类别:
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