Islets最新文献

{"title":"Beta-cell hubs maintain Ca²⁺ oscillations in human and mouse islet simulations.","authors":"Chon-Lok Lei,&nbsp;Joely A Kellard,&nbsp;Manami Hara,&nbsp;James D Johnson,&nbsp;Blanca Rodriguez,&nbsp;Linford J B Briant","doi":"10.1080/19382014.2018.1493316","DOIUrl":"https://doi.org/10.1080/19382014.2018.1493316","url":null,"abstract":"<p><p>Islet β-cells are responsible for secreting all circulating insulin in response to rising plasma glucose concentrations. These cells are a phenotypically diverse population that express great functional heterogeneity. In mice, certain β-cells (termed 'hubs') have been shown to be crucial for dictating the islet response to high glucose, with inhibition of these hub cells abolishing the coordinated Ca²⁺ oscillations necessary for driving insulin secretion. These β-cell hubs were found to be highly metabolic and susceptible to pro-inflammatory and glucolipotoxic insults. In this study, we explored the importance of hub cells in human by constructing mathematical models of Ca²⁺ activity in human islets. Our simulations revealed that hubs dictate the coordinated Ca²⁺ response in both mouse and human islets; silencing a small proportion of hubs abolished whole-islet Ca²⁺ activity. We also observed that if hubs are assumed to be preferentially gap junction coupled, then the simulations better adhere to the available experimental data. Our simulations of 16 size-matched mouse and human islet architectures revealed that there are species differences in the role of hubs; Ca²⁺ activity in human islets was more vulnerable to hub inhibition than mouse islets. These simulation results not only substantiate the existence of β-cell hubs, but also suggest that hubs may be favorably coupled in the electrical and metabolic network of the islet, and that targeted destruction of these cells would greatly impair human islet function.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 4","pages":"151-167"},"PeriodicalIF":2.2,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1493316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10055474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neprilysin inhibition in mouse islets enhances insulin secretion in a GLP-1 receptor dependent manner.","authors":"Nathalie Esser,&nbsp;Breanne M Barrow,&nbsp;Edwina Choung,&nbsp;Nancy J Shen,&nbsp;Sakeneh Zraika","doi":"10.1080/19382014.2018.1502521","DOIUrl":"https://doi.org/10.1080/19382014.2018.1502521","url":null,"abstract":"<p><p>Neprilysin, a widely expressed peptidase upregulated in type 2 diabetes, is capable of cleaving and inactivating the insulinotropic glucagon-like peptide-1 (GLP-1). Like dipeptidyl peptidase-4 (DPP-4), inhibition of neprilysin activity under diabetic conditions is associated with increased active GLP-1 levels and improved glycemic control. While neprilysin expression has been demonstrated in islets, its local contribution to GLP-1-mediated insulin secretion remains unknown. We investigated in vitro whether islet neprilysin inhibition enhances insulin secretion in response to glucose and/or exogenous GLP-1, and whether these effects are mediated by GLP-1 receptor (GLP-1R). Further, we compared the effect of neprilysin versus DPP-4 inhibition on insulin secretion. Isolated islets from wild-type (Glp1r^+/+) and GLP-1 receptor knockout (Glp1r^-/-) mice were incubated with or without the neprilysin inhibitor thiorphan and/or the DPP-4 inhibitor sitagliptin for 2.5 hours. During the last hour, insulin secretion was assessed in response to 2.8 mmol/l or 20 mmol/l glucose alone or plus exogenous active GLP-1. In Glp1r^+/+ islets, neprilysin inhibition enhanced 2.8 mmol/l and 20 mmol/l glucose- and GLP-1-mediated insulin secretion to the same extent as DPP-4 inhibition. These effects were blunted in Glp1r^-/- islets. In conclusion, inhibition of islet neprilysin in vitro increases glucose-mediated insulin secretion in a GLP-1R-dependent manner and enhances the insulinotropic effect of exogenous active GLP-1. Thus, neprilysin inhibitors may have therapeutic potential in type 2 diabetes by preserving islet-derived and circulating active GLP-1 levels.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 5","pages":"175-180"},"PeriodicalIF":2.2,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1502521","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36424663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse β cells and their translational relevance.","authors":"Maša Skelin Klemen, Jurij Dolenšek, Marjan Slak Rupnik, Andraž Stožer","doi":"10.1080/19382014.2017.1342022","DOIUrl":"10.1080/19382014.2017.1342022","url":null,"abstract":"<p><p>In β cells, stimulation by metabolic, hormonal, neuronal, and pharmacological factors is coupled to secretion of insulin through different intracellular signaling pathways. Our knowledge about the molecular machinery supporting these pathways and the patterns of signals it generates comes mostly from rodent models, especially the laboratory mouse. The increased availability of human islets for research during the last few decades has yielded new insights into the specifics in signaling pathways leading to insulin secretion in humans. In this review, we follow the most central triggering pathway to insulin secretion from its very beginning when glucose enters the β cell to the calcium oscillations it produces to trigger fusion of insulin containing granules with the plasma membrane. Along the way, we describe the crucial building blocks that contribute to the flow of information and focus on their functional role in mice and humans and on their translational implications.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"9 6","pages":"109-139"},"PeriodicalIF":2.2,"publicationDate":"2017-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/59/83/kisl-09-06-1342022.PMC5710702.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35129472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of different molecular forms of C. histolyticum class I collagenase to recover islets.","authors":"Michael L Green,&nbsp;Andrew G Breite,&nbsp;Caleb A Beechler,&nbsp;Francis E Dwulet,&nbsp;Robert C McCarthy","doi":"10.1080/19382014.2017.1365996","DOIUrl":"https://doi.org/10.1080/19382014.2017.1365996","url":null,"abstract":"<p><p>One factor that may contribute to variability between different lots of purified collagenase to recover islets is the molecular form of C. histolyticum class I (C1) collagenase used in the isolation procedure. Two different enzyme mixtures containing C1, class II (C2) collagenase and BP Protease were compared for their effectiveness to recover islets from split adult porcine pancreas. The same enzyme activities per g trimmed tissue were used for all isolations with the only difference being the mass of C1 required to achieve 25,000 collagen degradation activity U/g tissue. The results show no differences in performance of the two enzyme mixtures. The only significant difference is 19 fold more truncated C1 was required to achieve the same result as intact C1.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"9 6","pages":"177-181"},"PeriodicalIF":2.2,"publicationDate":"2017-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1365996","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35374189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of liver histopathology on islet cell engraftment in the model mimicking autologous islet cell transplantation.","authors":"Chirag S Desai,&nbsp;Khalid M Khan,&nbsp;Xiaobo Ma,&nbsp;Henghong Li,&nbsp;Juan Wang,&nbsp;Lijuan Fan,&nbsp;Guoling Chen,&nbsp;Jill P Smith,&nbsp;Wanxing Cui","doi":"10.1080/19382014.2017.1356558","DOIUrl":"https://doi.org/10.1080/19382014.2017.1356558","url":null,"abstract":"<p><strong>Background: </strong>The inflammatory milieu in the liver as determined by histopathology is different in individual patients undergoing autologous islet cell transplantation. We hypothesized that inflammation related to fatty-liver adversely impacts islet survival. To test this hypothesis, we used a mouse model of fatty-liver to determine the outcome of syngeneic islet transplantation after chemical pancreatectomy.</p><p><strong>Methods: </strong>Mice (C57BL/6) were fed a high-fat-diet from 6 weeks of age until attaining a weight of ≥28 grams (6-8 weeks) to produce a fatty liver (histologically > 30% fat);steatosis was confirmed with lipidomic profile of liver tissue. Islets were infused via the intra-portal route in fatty-liver and control mice after streptozotocin induction of diabetes. Outcomes were assessed by the rate of euglycemia, liver histopathology, evaluation of liver inflammation by measuring tissue cytokines IL-1β and TNF-α by RT-PCR and CD31 expression by immunohistochemistry.</p><p><strong>Results: </strong>The difference in the euglycemic fraction between the normal liver group (90%, 9/10) and the fatty-liver group (37.5%, 3/8) was statistically significant at the 18^th day post- transplant and was maintained to the end of the study (day 28) (p = 0.019, X² = 5.51). Levels of TNF-α and IL-1β were elevated in fatty-liver mice (p = 0.042, p = 0.037). Compared to controls cytokine levels were elevated after islet cell transplantation and in transplanted fatty-liver mice as compared to either fatty- or islet transplant group alone (p = NS). A difference in the histochemical pattern of CD31 could not be determined.</p><p><strong>Conclusion: </strong>Fatty-liver creates an inflammatory state which adversely affects the outcome of autologous islet cell transplantation.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"9 6","pages":"140-149"},"PeriodicalIF":2.2,"publicationDate":"2017-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1356558","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35507631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A proteome analysis of pig pancreatic islets and exocrine tissue by liquid chromatography with tandem mass spectrometry.","authors":"Yoshiki Nakashima,&nbsp;Chika Miyagi-Shiohira,&nbsp;Naoya Kobayashi,&nbsp;Issei Saitoh,&nbsp;Masami Watanabe,&nbsp;Hirofumi Noguchi","doi":"10.1080/19382014.2017.1389826","DOIUrl":"https://doi.org/10.1080/19382014.2017.1389826","url":null,"abstract":"<p><p>Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is a proteome analysis method, and the shotgun analysis by LC-MS/MS comprehensively identifies proteins from tissues and cells with high resolving power. In this study, we analyzed the protein expression in pancreatic tissue by LC-MS/MS. Islets isolated from porcine pancreata (purity ≥95%) and exocrine tissue (purity ≥99%) were used in this study. LC-MS/MS showed that 13 proteins were expressed in pancreatic islets only (Group I), 43 proteins were expressed in both islets and exocrine tissue (Group I&E), and 102 proteins were expressed in exocrine tissue only (Group E). Proteins involved in islet differentiation and cell proliferation were identified in Group I (e.g. CLUS, CMGA, MIF). In addition, various functional proteins (e.g. SCG2, TBA1A) were identified in islet by using the new method of 'principal component analysis (PCA)'. However, the function of such proteins on islets remains unclear. EPCAM was identified in Group E. Group E was found to include proteins involved in clinical inflammatory diseases such as pancreatitis (e.g. CBPA1, CGL, CYTB, ISK1 and PA21B). Many of these identified proteins were reported less frequently in previous studies, and HS71B, NEC2, PRAF3 and SCG1 were newly detected in Group I while CPNS1, DPEP1, GANAB, GDIB, GGT1, HSPB1, ICTL, VILI, MUTA, NDKB, PTGR1, UCHL3, VAPB and VINC were newly detected in Group E. These results show that comprehensive expression analysis of proteins by LC-MS/MS is useful as a method to investigate new factors constructing cellular component, biological process, and molecular function.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"9 6","pages":"159-176"},"PeriodicalIF":2.2,"publicationDate":"2017-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1389826","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35219985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular-derived connective tissue growth factor (Ctgf) is critical for pregnancy-induced β cell hyperplasia in adult mice.","authors":"Raymond C Pasek,&nbsp;Jennifer C Dunn,&nbsp;Joseph M Elsakr,&nbsp;Mounika Aramandla,&nbsp;Anveetha R Matta,&nbsp;Maureen Gannon","doi":"10.1080/19382014.2017.1356963","DOIUrl":"https://doi.org/10.1080/19382014.2017.1356963","url":null,"abstract":"<p><p>During pregnancy, maternal β cells undergo compensatory changes including hypertrophy, hyperplasia, and increased glucose-stimulated insulin secretion (GSIS). Failure of these adaptations to occur can result in gestational diabetes mellitus. The secreted protein, Connective tissue growth factor (Ctgf), is critical for normal β cell development and promotes regeneration after partial β cell ablation. During embryogenesis, Ctgf is expressed in pancreatic ducts, vasculature, and β cells. In the adult pancreas, Ctgf is expressed only in the vasculature. Here, we report that pregnant mice with global Ctgf haploinsufficiency (Ctgf^LacZ/+) have an impairment in maternal β cell proliferation, while β cell proliferation in virgin Ctgf^LacZ/+ females is unaffected. Additionally, α-cell proliferation, β cell size, and GSIS were unaffected in Ctgf^LacZ/+ mice, suggesting that vascular-derived Ctgf has a specific role in islet compensation during pregnancy.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"9 6","pages":"150-158"},"PeriodicalIF":2.2,"publicationDate":"2017-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1356963","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35579241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexins and microRNAs: Interlinked players in regulating islet function?","authors":"Malati R Umrani, Mugdha V Joglekar, Ella Somerville Glover, Wilson Wong, Anandwardhan A Hardikar","doi":"10.1080/19382014.2017.1331192","DOIUrl":"10.1080/19382014.2017.1331192","url":null,"abstract":"ABSTRACT Pancreatic β-cells are connected to neighboring endocrine cells through the adherin proteins and gap junctions. Connexin 36 (Cx36) is one of the most well-studied and abundantly expressed gap-junction proteins within rodent islets, which is important in coordinated insulin secretion. The expression of connexins is regulated at various levels and by several mechanisms; one of which is via microRNAs. In past 2 decades, microRNAs (miRNAs) have emerged as key molecules in developmental, physiologic and pathological processes. However, very few studies have demonstrated miRNA-mediated regulation of connexins. Even though there are no reports yet on miRNAs and Cx36; we envisage that considering the important role of connexins and microRNAs in insulin secretion, there would be common pathways interlinking these biomolecules. Here, we discuss the current literature on connexins and miRNAs specifically with reference to islet function.","PeriodicalId":14671,"journal":{"name":"Islets","volume":"9 5","pages":"99-108"},"PeriodicalIF":2.2,"publicationDate":"2017-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1331192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35150929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of mesenchymal stem cells into islet cell spheroids improves long-term viability, but not islet function.","authors":"Sonia Rawal,&nbsp;S Janette Williams,&nbsp;Karthik Ramachandran,&nbsp;Lisa Stehno-Bittel","doi":"10.1080/19382014.2017.1341455","DOIUrl":"https://doi.org/10.1080/19382014.2017.1341455","url":null,"abstract":"<p><p>Pancreatic islets, especially the large islets (> 150µm in diameter) have poor survival rates in culture. Co-culturing with mesenchymal stem cells (MSCs) has been shown to improve islet survival and function. However, most co-culture studies have been comprised of MSC surrounding islets in the media. The purpose of this study was to determine whether islet survival and function was improved when the 2 populations of cells were intermingled with each other in a defined geometry. Hybrid spheroids containing 25, 50 or 75 or 90% islets cells with appropriate numbers of MSCs were created along with spheroids comprised of only islet cells or only MSCs. Spheroids were tested for yield, viability, diameter, cellular composition, and glucose-stimulated insulin secretion. The 25% islet/75% MSC group created the fewest spheroids, with the poorest survival and insulin secretion and the largest diameter. The remaining groups were highly viable with average diameters under 80µm at formation. However, the hybrid spheroid groups preferred to cluster in islet-only spheroids. The 50, 75 and 90% islet cell groups had excellent long-term survival with 90-95% viability at 2 weeks in culture, compared with the islet only group that were below 80% viability. The glucose-stimulated insulin secretion was not statistically different for the 50, 75, or 90 groups when exposed to 2.4, 16.8, or 22.4 mM glucose. Only the spheroids with 25% islet cells had a statistically lower levels of insulin release, and the 100% had statistically higher levels at 22.4 mM glucose and in response to secretagogue. Thus, imbedded co-culture improved long-term viability, but failed to enhance glucose-stimulated insulin secretion in vitro.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"9 5","pages":"87-98"},"PeriodicalIF":2.2,"publicationDate":"2017-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1341455","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35129471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of additives, scaffolds and extracellular matrix components for improvement of human pancreatic islet outcomes in vitro: A systematic review.","authors":"Natália Emerim Lemos,&nbsp;Letícia de Almeida Brondani,&nbsp;Cristine Dieter,&nbsp;Jakeline Rheinheimer,&nbsp;Ana Paula Bouças,&nbsp;Cristiane Bauermann Leitão,&nbsp;Daisy Crispim,&nbsp;Andrea Carla Bauer","doi":"10.1080/19382014.2017.1335842","DOIUrl":"10.1080/19382014.2017.1335842","url":null,"abstract":"<p><p>Pancreatic islet transplantation is an established treatment to restore insulin independence in type 1 diabetic patients. Its success rates have increased lately based on improvements in immunosuppressive therapies and on islet isolation and culture. It is known that the quality and quantity of viable transplanted islets are crucial for the achievement of insulin independence and some studies have shown that a significant number of islets are lost during culture time. Thus, in an effort to improve islet yield during culture period, researchers have tested a variety of additives in culture media as well as alternative culture devices, such as scaffolds. However, due to the use of different categories of additives or devices, it is difficult to draw a conclusion on the benefits of these strategies. Therefore, the aim of this systematic review was to summarize the results of studies that described the use of medium additives, scaffolds or extracellular matrix (ECM) components during human pancreatic islets culture. PubMed and Embase repositories were searched. Of 5083 articles retrieved, a total of 37 articles fulfilled the eligibility criteria and were included in the review. After data extraction, articles were grouped as follows: 1) \"antiapoptotic/anti-inflammatory/antioxidant,\" 2) \"hormone,\" 3) \"sulphonylureas,\" 4) \"serum supplements,\" and 5) \"scaffolds or ECM components.\" The effects of the reviewed additives, ECM or scaffolds on islet viability, apoptosis and function (glucose-stimulated insulin secretion - GSIS) were heterogeneous, making any major conclusion hard to sustain. Overall, some \"antiapoptotic/anti-inflammatory/antioxidant\" additives decreased apoptosis and improved GSIS. Moreover, islet culture with ECM components or scaffolds increased GSIS. More studies are needed to define the real impact of these strategies in improving islet transplantation outcomes.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"9 5","pages":"73-86"},"PeriodicalIF":2.2,"publicationDate":"2017-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1335842","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35143406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}