Diabetes Mellitus Drives Extracellular Vesicle Secretion and Promotes Increased Internalization by Circulating Leukocytes
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ABSTRACT:
PROVIDER: PRJNA415016 | ENA |
REPOSITORIES: ENA
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Project description:Type 2 diabetes mellitus is a chronic age-associated degenerative metabolic disease that reflects relative insulin deficiency and resistance. Extracellular vesicles (EVs; exosomes, microvesicles and apoptotic bodies) are small (50-400 nM) lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids as part of intercellular communication systems. Recent studies in mouse models and in cell culture suggest that EVs may modulate insulin signaling. We designed a longitudinal and cross-sectional cohort of euglycemic, pre-diabetic and diabetic participants. Diabetic individuals had significantly higher levels of EVs in their circulation than euglycemic controls. We found that insulin resistance increases EV secretion through an autophagy-dependent mechanism. Furthermore, the levels of several proteins involved in insulin signaling were altered in EVs from individuals with high levels of insulin resistance and β-cell dysfunction. Moreover, EVs from diabetic individuals were preferentially internalized by circulating leukocytes. Microarray of these leukocytes revealed altered gene expression pathways related to cell survival, oxidative stress and immune function. Collectively, these results suggest that insulin resistance increases the secretion of EVs, which are preferential internalized by leukocytes and whose gene expression is subsequently altered by the internalized EVs.
2018-10-22 | GSE105167 | GEO
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM. Total RNA from L-Δprkar1a KO mice compared to control D-glucose mice
2014-04-01 | E-GEOD-48815 | biostudies-arrayexpress
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM.
2014-04-01 | GSE48815 | GEO
Project description:Spermidine synthase regulates extracellular vesicle secretion in castration resistant prostate cancer.
| PRJNA600204 | ENA
Project description:Optimizing Cell Therapy by Sorting Cells with High Extracellular Vesicle Secretion
| PRJNA1005988 | ENA
Project description:Cells release lipid-bound extracellular vesicles (EVs; exosomes, microvesicles and apoptotic bodies) containing proteins, lipids and RNAs into the circulation. Vesicles mediate intercellular communication between both neighboring and distant cells. There is substantial interest in using EVs as biomarkers for age-related diseases including cancer, and neurodegenerative, metabolic and cardiovascular diseases. The majority of research focuses on identifying differences in EVs when comparing disease states and matched controls. Here, we analyzed circulating plasma EVs in a cross-sectional and longitudinal study in order to address age-related changes in community-dwelling individuals. We found that EV concentration decreases with advancing age. Furthermore, EVs from older individuals were more readily internalized by B cells and increased MHC-II expression on monocytes compared with EVs from younger individuals, indicating that the decreased concentration of EVs with age may be due in part to increased internalization. EVs activated both monocytes and B cells, and activation of B cells by LPS enhanced EV internalization. We also report a relative stability of EV concentration and protein amount in individual subjects over time. Our data provide important information towards establishing a profile of EVs with human age, which will further aid in the development of EV-based diagnostics for aging and age-related diseases.
| S-EPMC5430958 | biostudies-literature
Project description:Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of microRNAs (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 improves insulin secretion and glucose intolerance in db/db mice. Supporting the function of EVs’ miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs shows their distribution in mouse pancreatic islets. Tracing the injected AAV-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat results in upregulating miR-27a-5p in EVs and serum, and elicits mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolishes the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EVs’ miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus.
2024-12-04 | GSE271706 | GEO
Project description:Human macrophages secrete extracellular vesicles loaded with numerous immunoregulatory proteins. Here we employed high throughput quantitative proteomics to characterize the modulation of vesicle-mediated protein secretion during non-canonical caspase-4/5-dependent inflammasome activation. We show that human macrophages activate robust caspase-4- dependent extracellular vesicle secretion upon transfection of LPS, and this process is also partially dependent on NLRP-3 and caspase-5. Similar effect occurs with delivery of the LPS with E. coli-derived outer membrane vesicles. Moreover, sensitization of the macrophages through TLR4 prior to LPS transfection dramatically augments the EV-mediated protein secretion. Our data demonstrate that this process differs significantly from ATP-induced vesiculation, and is dependent on autocrine interferon signal associated with TLR4 activation. TLR4 activation preceding the non-canonical inflammasome activation significantly enhances vesicle-mediated secretion of inflammasome components caspase-1, ASC and lytic cell death effectors GSDMD, MLKL and NINJ1, suggesting that inflammatory EV transfer may exert paracrine effects in recipient cells. Moreover, using bioinformatic methods, we identify 15-deoxy-delta-12,14-prostaglandin J2 and parthenolide as inhibitors of caspase-4-mediated inflammation and vesicle secretion, indicating potential new therapeutic potential of these anti-inflammatory drugs.
2022-12-01 | PXD033002 | Pride
Project description:Nanoparticle Internalization Promotes the Survival of Primary Macrophages
| PRJNA679953 | ENA