IsletsPub Date : 2018-01-02Epub Date: 2017-12-22DOI: 10.1080/19382014.2017.1405189
Danielle J Borg, Felicia Y T Yap, Sahar Keshvari, David G Simmons, Linda A Gallo, Amelia K Fotheringham, Aowen Zhuang, Robyn M Slattery, Sumaira Z Hasnain, Melinda T Coughlan, Phillip Kantharidis, Josephine M Forbes
{"title":"Perinatal exposure to high dietary advanced glycation end products in transgenic NOD8.3 mice leads to pancreatic beta cell dysfunction.","authors":"Danielle J Borg, Felicia Y T Yap, Sahar Keshvari, David G Simmons, Linda A Gallo, Amelia K Fotheringham, Aowen Zhuang, Robyn M Slattery, Sumaira Z Hasnain, Melinda T Coughlan, Phillip Kantharidis, Josephine M Forbes","doi":"10.1080/19382014.2017.1405189","DOIUrl":"10.1080/19382014.2017.1405189","url":null,"abstract":"<p><p>The contribution of environmental factors to pancreatic islet damage in type 1 diabetes remains poorly understood. In this study, we crossed mice susceptible to type 1 diabetes, where parental male (CD8<sup>+</sup> T cells specific for IGRP<sub>206-214</sub>; NOD8.3) and female (NOD/ShiLt) mice were randomized to a diet either low or high in AGE content and maintained on this diet throughout pregnancy and lactation. After weaning, NOD8.3<sup>+</sup> female offspring were identified and maintained on the same parental feeding regimen for until day 28 of life. A low AGE diet, from conception to early postnatal life, decreased circulating AGE concentrations in the female offspring when compared to a high AGE diet. Insulin, proinsulin and glucagon secretion were greater in islets isolated from offspring in the low AGE diet group, which was akin to age matched non-diabetic C57BL/6 mice. Pancreatic islet expression of Ins2 gene was also higher in offspring from the low AGE diet group. Islet expression of glucagon, AGEs and the AGE receptor RAGE, were each reduced in low AGE fed offspring. Islet immune cell infiltration was also decreased in offspring exposed to a low AGE diet. Within pancreatic lymph nodes and spleen, the proportions of CD4<sup>+</sup> and CD8<sup>+</sup> T cells did not differ between groups. There were no significant changes in body weight, fasting glucose or glycemic hormones. This study demonstrates that reducing exposure to dietary AGEs throughout gestation, lactation and early postnatal life may benefit pancreatic islet secretion and immune infiltration in the type 1 diabetic susceptible mouse strain, NOD8.3.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 1","pages":"10-24"},"PeriodicalIF":2.2,"publicationDate":"2018-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1405189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35622524","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}
IsletsPub Date : 2018-01-02Epub Date: 2018-01-09DOI: 10.1080/19382014.2017.1405202
Greg G Kojayan, Michael Alexander, David K Imagawa, Jonathan R T Lakey
{"title":"Systematic review of islet cryopreservation.","authors":"Greg G Kojayan, Michael Alexander, David K Imagawa, Jonathan R T Lakey","doi":"10.1080/19382014.2017.1405202","DOIUrl":"https://doi.org/10.1080/19382014.2017.1405202","url":null,"abstract":"<p><p>Pancreatic islet transplantation is being extensively researched as an alternative treatment for type 1 diabetic patients. This treatment is currently limited by temporal mismatch, between the availability of pancreas and isolated islets from deceased organ donor, and the recipient's need for freshly isolated islets. To solve this issue, cryopreservation of islets may offer the potential to bank islets for transplant on demand. Cryopreservation, however, introduces an overwhelmingly harsh environment to the ever-so-fragile islets. After exposure to the freezing and thawing, islets are usually either apoptotic, non-functional, or non-viable. Several studies have proposed various techniques that could lead to increased cell survival and function following a deep freeze. The purpose of this article is to critically review the techniques of islet cryopreservation, with the goal of highlighting optimization parameters that can lead to the most viable and functional islet upon recovery and/or transplant.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 1","pages":"40-49"},"PeriodicalIF":2.2,"publicationDate":"2018-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1405202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35721237","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}
IsletsPub Date : 2018-01-01Epub Date: 2018-08-17DOI: 10.1080/19382014.2018.1503027
Michael J Jurczak, Saumya Saini, Simona Ioja, Diana K Costa, Nnamdi Udeh, Xiaojian Zhao, Jean M Whaley, Richard G Kibbey
{"title":"SGLT2 knockout prevents hyperglycemia and is associated with reduced pancreatic β-cell death in genetically obese mice.","authors":"Michael J Jurczak, Saumya Saini, Simona Ioja, Diana K Costa, Nnamdi Udeh, Xiaojian Zhao, Jean M Whaley, Richard G Kibbey","doi":"10.1080/19382014.2018.1503027","DOIUrl":"https://doi.org/10.1080/19382014.2018.1503027","url":null,"abstract":"<p><p>Inhibition of the sodium-glucose co-transporter type 2 (SGLT2) has received growing acceptance as a novel, safe and effective means to improve glycemic control in patients with type 2 diabetes. Inhibition of SGLT2 lowers the renal glucose threshold and reduces plasma glucose by promoting glucose excretion in urine. Both animal studies and clinical trials in man suggest that SGLT2 inhibition has the potential to improve pancreatic β-cell function by reducing glucose toxicity. However, there is limited data exploring how reducing glucotoxicity via SGLT2 inhibition affects rates of β-cell proliferation and death throughout life in the context of insulin resistance and type 2 diabetes. SGLT2<sup>-/-</sup> mice were backcrossed to the db/db strain to produce littermate control db/db-SGLT2<sup>+/+</sup> and experimental db/db-SGLT2<sup>-/-</sup> mice. Mice were euthanized at 5, 12 and 20 weeks of age to collect plasma for glucose, insulin, lipid and cytokine measures, and pancreata for histological analysis including determination of β-cell mass and rates of proliferation and death. SGLT2 deletion in db/db mice reduced plasma glucose as early as 5 weeks of age and continued throughout life without changes in plasma lipids or cytokines. Reduced plasma glucose levels occurred in parallel with an increase in the relative β-cell volume and reduced frequency of β-cell death, and no apparent change in rates of β-cell proliferation. These data add to a growing body of evidence demonstrating that improved glycemic control achieved through SGLT2 inhibition can preserve β-cell function and endogenous insulin secretion by reducing glucose toxicity and rates of β-cell death.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":" ","pages":"181-189"},"PeriodicalIF":2.2,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1503027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40555253","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}
IsletsPub Date : 2018-01-01Epub Date: 2018-08-15DOI: 10.1080/19382014.2018.1480285
Edith J Arany, Muhammad Waseem, Brenda J Strutt, Astrid Chamson-Reig, Adam Bernardo, Elizabeth Eng, David J Hill
{"title":"Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice.","authors":"Edith J Arany, Muhammad Waseem, Brenda J Strutt, Astrid Chamson-Reig, Adam Bernardo, Elizabeth Eng, David J Hill","doi":"10.1080/19382014.2018.1480285","DOIUrl":"https://doi.org/10.1080/19382014.2018.1480285","url":null,"abstract":"<p><p>Both bone marrow-derived hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) improve glycemic control in diabetic mice, but their kinetics and associated changes in pancreatic morphology have not been directly compared. Our goal was to examine the time course of improvements in glucose tolerance and associated changes in β-cell mass and proliferation following transplantation of equivalent numbers of HSC or MSC from the same bone marrow into diabetic non-obese diabetic severe combined immune deficiency (NOD.SCID) mice. We used transgenic mice with a targeted expression of yellow fluorescent protein (YFP) driven by the Vav1 gene promoter to genetically tag HSC and progeny. HSC were separated from bone marrow by fluorescence-activated cell sorting and MSC following cell culture. Equivalent numbers of isolated HSC or MSC were transplanted directly into the pancreas of NOD.SCID mice previously made diabetic with streptozotocin. Glucose tolerance, serum insulin, β-cell mass and β-cell proliferation were examined up to 28 days following transplant. Transplantation with MSC improved glucose tolerance within 7 days and serum insulin levels increased, but with no increase in β-cell mass. Mice transplanted with HSC showed improved glucose tolerance only after 3 weeks associated with increased β-cell proliferation and mass. We conclude that single injections of either MSC or HSC transiently improved glycemic control in diabetic NOD.SCID mice, but with different time courses. However, only HSC infiltrated the islets and were associated with an expanded β-cell mass. This suggests that MSC and HSC have differing mechanisms of action.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":" ","pages":"137-150"},"PeriodicalIF":2.2,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1480285","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36400876","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}
IsletsPub Date : 2018-01-01Epub Date: 2018-10-12DOI: 10.1080/19382014.2018.1513748
Nidheesh Dadheech, Dominique Garrel, Jean Buteau
{"title":"Evidence of unrestrained beta-cell proliferation and neogenesis in a patient with hyperinsulinemic hypoglycemia after gastric bypass surgery.","authors":"Nidheesh Dadheech, Dominique Garrel, Jean Buteau","doi":"10.1080/19382014.2018.1513748","DOIUrl":"https://doi.org/10.1080/19382014.2018.1513748","url":null,"abstract":"<p><p>Hyperinsulinemic hypoglycemia syndrome (HIHG) is a rare complication of roux-en-Y gastric bypass surgery. The pathology is associated with an excessive function of pancreatic beta-cells, and requires pancreas resection in patients that are recalcitrant to nutritional and pharmacological interventions. The exact prevalence is not clearly understood and the underlying mechanisms not yet fully characterized. We herein sought to perform histological and molecular examination of pancreatic sections obtained from a patient who developed HIHG as a complication of gastric bypass compared to 3 weight-matched controls. We studied markers of cellular replication and beta-cell differentiation by immunohistochemistry and immunofluorescence. HIHG after gastric bypass was characterized by a profound increase in beta-cell mass. Cellular proliferation was increased in islets and ducts compared to controls, suggesting unrestrained proliferation in HIHG. We also detected beta-cell differentiation markers in duct cells and occasional duct cells displaying both insulin and glucagon immunoreactivity. These histological observations suggest that beta-cell differentiation from ductal progenitor cells could also underly beta-cell mass expansion in HIHG. Altogether, our results can be construed to demonstrate that HIHG after gastric bypass is characterized by abnormal beta-cell mass expansion, resulting from both unrestrained beta-cell replication and neogenesis.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 6","pages":"213-220"},"PeriodicalIF":2.2,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1513748","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36567447","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}
IsletsPub Date : 2018-01-01Epub Date: 2018-12-06DOI: 10.1080/19382014.2018.1540234
Reka Lorincz, Christopher H Emfinger, Andrea Walcher, Michael Giolai, Claudia Krautgasser, Maria S Remedi, Colin G Nichols, Dirk Meyer
{"title":"In vivo monitoring of intracellular Ca<sup>2+</sup> dynamics in the pancreatic β-cells of zebrafish embryos.","authors":"Reka Lorincz, Christopher H Emfinger, Andrea Walcher, Michael Giolai, Claudia Krautgasser, Maria S Remedi, Colin G Nichols, Dirk Meyer","doi":"10.1080/19382014.2018.1540234","DOIUrl":"https://doi.org/10.1080/19382014.2018.1540234","url":null,"abstract":"<p><p>Assessing the response of pancreatic islet cells to glucose stimulation is important for understanding β-cell function. Zebrafish are a promising model for studies of metabolism in general, including stimulus-secretion coupling in the pancreas. We used transgenic zebrafish embryos expressing a genetically-encoded Ca<sup>2+</sup> sensor in pancreatic β-cells to monitor a key step in glucose induced insulin secretion; the elevations of intracellular [Ca<sup>2+</sup>]<sub>i</sub>. In vivo and ex vivo analyses of [Ca<sup>2+</sup>]<sub>i</sub> demonstrate that β-cell responsiveness to glucose is well established in late embryogenesis and that embryonic β-cells also respond to free fatty acid and amino acid challenges. In vivo imaging of whole embryos further shows that indirect glucose administration, for example by yolk injection, results in a slow and asynchronous induction of β-cell [Ca<sup>2+</sup>]<sub>i</sub> responses, while intravenous glucose injections cause immediate and islet-wide synchronized [Ca<sup>2+</sup>]<sub>i</sub> fluctuations. Finally, we demonstrate that embryos with disrupted mutation of the Ca<sub>V</sub>1.2 channel gene cacna1c are hyperglycemic and that this phenotype is associated with glucose-independent [Ca<sup>2+</sup>]<sub>i</sub> fluctuation in β-cells. The data reveal a novel central role of cacna1c in β-cell specific stimulus-secretion coupling in zebrafish and demonstrate that the novel approach we propose - to monitor the [Ca<sup>2+</sup>]<sub>i</sub> dynamics in embryonic β-cells in vivo - will help to expand the understanding of β-cell physiological functions in healthy and diseased states.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 6","pages":"221-238"},"PeriodicalIF":2.2,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1540234","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36755863","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":"Patient and family expectations of beta-cell replacement therapies in type 1 diabetes.","authors":"Akitsu Kawabe, Shinichi Matsumoto, Masayuki Shimoda","doi":"10.1080/19382014.2018.1503518","DOIUrl":"https://doi.org/10.1080/19382014.2018.1503518","url":null,"abstract":"<p><strong>Background: </strong>New methods of beta-cell replacement have been developed to maintain excellent glycemic control, improve quality of life, and even eliminate insulin injections in patients with type 1 diabetes mellitus (T1DM). Previously, we demonstrated that being insulin-free is the strongest motivation for accepting a newly developed therapy. Multiple allogeneic islet transplantations with immunosuppression using a human donor is the best option to be insulin-free, but the necessity for immunosuppression and donor shortage are major issues. However, these issues have been improved with scientific progress. The aim of this study was to investigate the opinions of patients and their families about the current progress.</p><p><strong>Methods: </strong>We conducted a questionnaire survey of T1DM patients (n = 47) and their family members (n = 49) about newly developed therapies: single and multiple allogeneic islet transplantation, single and multiple encapsulated allogeneic islet transplantation, single and multiple xenogeneic islet transplantation, and induced pluripotent stem cell therapy.</p><p><strong>Results: </strong>More than 90% of respondents wished to be insulin-free and have stable glycemic control. More than 90% of respondents accepted at least one of the new therapies. The current standard treatment multiple allogeneic islet transplantation was not well accepted or favored.</p><p><strong>Conclusions: </strong>The next generation of treatments, including xenotransplantation and induced pluripotent stem cell therapy, were more acceptable and favorable. Even though the majority of patients wish to become insulin-free, it is not sufficiently strong motivation for accepting newly developed treatments.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":" ","pages":"190-200"},"PeriodicalIF":2.2,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1503518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40442558","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}
IsletsPub Date : 2018-01-01Epub Date: 2018-07-19DOI: 10.1080/19382014.2018.1451281
Jack Williams, Nicholas Jacus, Kevin Kavalackal, Kirstie K Danielson, Rebecca S Monson, Yong Wang, Jose Oberholzer
{"title":"Over ten-year insulin independence following single allogeneic islet transplant without T-cell depleting antibody induction.","authors":"Jack Williams, Nicholas Jacus, Kevin Kavalackal, Kirstie K Danielson, Rebecca S Monson, Yong Wang, Jose Oberholzer","doi":"10.1080/19382014.2018.1451281","DOIUrl":"https://doi.org/10.1080/19382014.2018.1451281","url":null,"abstract":"<p><p>Islet cell transplantation is a promising functional cure for type 1 diabetes; however, maintaining long-term islet graft function and insulin independence is difficult to achieve. In this short report we present a patient with situs inversus, who at the time of islet transplantation had a 26-year history of type 1 diabetes, complicated by hypoglycemic unawareness and severe hypoglycemic events. After a single allogeneic islet transplant of a low islet mass, and despite developing de novo anti-insulin and anti-GAD65 autoantibodies, the patient has remarkably maintained insulin independence with tight glycemic control and normal metabolic profiles for 10 years, after receiving prolonged non-T-cell depleting immunosuppression.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":" ","pages":"168-174"},"PeriodicalIF":2.2,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1451281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36327901","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}
IsletsPub Date : 2018-01-01DOI: 10.1080/19382014.2018.1493316
Chon-Lok Lei, Joely A Kellard, Manami Hara, James D Johnson, Blanca Rodriguez, Linford J B Briant
{"title":"Beta-cell hubs maintain Ca<sup>2+</sup> oscillations in human and mouse islet simulations.","authors":"Chon-Lok Lei, Joely A Kellard, Manami Hara, James D Johnson, Blanca Rodriguez, Linford J B Briant","doi":"10.1080/19382014.2018.1493316","DOIUrl":"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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> activity in human islets. Our simulations revealed that hubs dictate the coordinated Ca<sup>2+</sup> response in both mouse and human islets; silencing a small proportion of hubs abolished whole-islet Ca<sup>2+</sup> 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; Ca<sup>2+</sup> 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":1.9,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113907/pdf/","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, Breanne M Barrow, Edwina Choung, Nancy J Shen, 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<sup>+/+</sup>) and GLP-1 receptor knockout (Glp1r<sup>-/-</sup>) 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<sup>+/+</sup> 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<sup>-/-</sup> 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}