Islets最新文献

{"title":"Evaluation of collagenase gold plus BP protease in isolating islets from human pancreata.","authors":"Bashar Khiatah,&nbsp;Amber Tucker,&nbsp;Kuan-Tsen Chen,&nbsp;Rachel Perez,&nbsp;Shiela Bilbao,&nbsp;Luis Valiente,&nbsp;Leonard Medrano,&nbsp;Jeffrey Rawson,&nbsp;Elena Forouhar,&nbsp;Keiko Omori,&nbsp;Fouad Kandeel,&nbsp;Meirigeng Qi,&nbsp;Ismail H Al-Abdullah","doi":"10.1080/19382014.2017.1417716","DOIUrl":"https://doi.org/10.1080/19382014.2017.1417716","url":null,"abstract":"<p><p>Selection of enzymes for optimal pancreas digestion is essential for successful human islet isolations. The aim of this study was to evaluate the efficacy and outcome of using Collagenase Gold plus BP protease (VitaCyte) (n = 8) by comparing it to two commercially available enzymes, Liberase MTF C/T (Roche) (n = 48) and Collagenase NB1/NP (Serva) (n = 15). The isolation outcomes were assessed by islet counting, viability, glucose-stimulated oxygen consumption rate (OCR), and successful graft-rate following transplantation in diabetic NOD scid mice. The pancreas donor characteristics were not significantly different between the tested enzyme groups regarding their BMI, pancreas weight, cold ischemia time (CIT) and HbA1c. The results show that digested tissue volume was not statistically significant between the VitaCyte enzyme (34.25 ± 5.4 mL) and the Roche enzyme (55.25 ± 3.42 mL, p = 0.073), however, this was significant with Serva enzyme (64.07 ± 7.95 mL, p = 0.020). Interestingly, the islet yields were not statistically different between all enzyme groups. Moreover, when islets were transplanted into NOD scid mice, the reversal rate of diabetes for the VitaCyte enzyme group was similar to all enzyme groups. In conclusion, the effectiveness of Collagenase Gold plus BP protease is comparable to the MTF C/T and the Collagenase NB1/NP enzymes; the low cost could facilitate the use of more pancreata for islet isolations.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 2","pages":"51-59"},"PeriodicalIF":2.2,"publicationDate":"2018-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1417716","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35777845","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":"Collagen type VI interaction improves human islet survival in immunoisolating microcapsules for treatment of diabetes.","authors":"L Alberto Llacua, Arjan Hoek, Bart J de Haan, Paul de Vos","doi":"10.1080/19382014.2017.1420449","DOIUrl":"10.1080/19382014.2017.1420449","url":null,"abstract":"<p><p>Collagens are the most abundant fibrous protein in the human body and constitute the main structural element of the extracellular matrix. It provides mechanical and physiological support for cells. In the pancreas, collagen VI content is more than double that of collagen I or IV. It is a major component of the islet-exocrine interface and could be involved in islet-cell survival. To test the impact of collagen VI on human encapsulated pancreatic islets-cells, we tested the effects of exogenous collagen type VI on in vitro functional survival of alginate encapsulated human islet-cells. Concentrations tested ranged from 0.1 to 50 µg/ml. Islets in capsules without collagen type VI served as control. Islet-cell interaction with collagen type VI at concentrations of 0.1 and 10 µg/ml, promoted islet-cell viability (p<0.05). Although no improvement in glucose induced insulin secretion (GSIS) was observed, islets in capsules without incorporation of collagen type VI showed more dysfunction and oxygen consumption rates was improved by inclusion of collagen type VI. Our results demonstrate that incorporation of collagen type VI in immunoisolated human islets supports in vitro viability and survival of human pancreatic islets.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 2","pages":"60-68"},"PeriodicalIF":2.2,"publicationDate":"2018-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1420449","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35898376","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 adverse effects of chronic low-dose exposure to nonylphenol on type 2 diabetes mellitus in high sucrose-high fat diet-treated rats.","authors":"Jie Yu,&nbsp;Jin Yang,&nbsp;Ya Luo,&nbsp;Yang Mengxue,&nbsp;Wenmei Li,&nbsp;Yu Yang,&nbsp;Liting He,&nbsp;Jie Xu","doi":"10.1080/19382014.2017.1404211","DOIUrl":"https://doi.org/10.1080/19382014.2017.1404211","url":null,"abstract":"<p><strong>Objectives: </strong>Although it has been shown that exposure to environmental endocrine disruptors (EDCs) has been implicated as a potential risk factor for metabolic disease, information on adverse effect of chronic low-dose exposure to nonylphenol (NP), on the development and progress of type 2 diabetes mellitus (T2DM) is scarce. NP, as an EDC, is a ubiquitous degradation product of nonylphenol polyethoxylate (NPE) that is primarily used in cleaning and industrial processes.</p><p><strong>Method: </strong>Eighty Sprague-Dawley rats were assigned into 8 groups (n = 10 per group): rats fed a normal-diet (ND) as the control (C-ND); rats fed a normal diet and were gavaged with NP at a dose level of 0.02 μg/kg/day (NP-L-ND), 0.2 μg/kg/day (NP-M-ND) or 2 μg/kg/day (NP-H-ND), respectively; rats fed a high-sucrose/high-fat diet (HSHFD) as the HSHFD control (C-HSHFD); rats fed a HSHFD and were gavaged with NP at a dose level of 0.02 μg/kg/day (NP-L-HSHFD), 0.2 μg/kg/day (NP-M-HSHFD) or 2 μg/kg/day (NP-H-HSHFD), respectively.</p><p><strong>Result: </strong>On day 180, the rats in the groups treated with NP-M-HSHFD and NP-H-HSHFD showed significant increases in body weight (p < 0.05) in comparison with the C-ND group. Fast blood glucose (FBG) level in the NP-M-HSHFD and NP-H-HSHFD groups was higher than that in the C-ND group (F = 96.17, p < 0.001). The fast serum insulin (FINS) level of rats was lower in both the NP-M-HSHFD and NP-H-HSHFD groups compared with the C-ND group (F = 145.56, p < 0.001). Serum leptin (LEP) level in both the NP-M-HSHFD and NP-H-HSHFD groups was lower when compared with the C-ND group (F = 34.62, p < 0.001). The effect of NP at the dose level of 0.2 μg/kg/day on FBG, serum FINS and LEP levels in rats was greatest among the treatment groups (p < 0.05). Oral glucose tolerance test showed increased area under the curve (AUC) in treatment groups at week 12 (p < 0.05). A decrease of pancreatic islet numbers and size was exhibited in the pancreatic tissue of NP-M-HSHFD and NP-H-HSHFD treated rats compared with C-ND treated rats. Co-exposure to NP and HSHFD causes inflammatory changes histologically.</p><p><strong>Conclusion: </strong>Chronic low-dose exposure to NP might induce impaired glucose tolerance, which further lead to insulin resistance, and pancreatic β cell insulin secretion deficiency, ultimately increase the risk of T2DM. Moreover, additive toxic effects of NP and HSHFD on pancreatic beta-cell function and glucose metabolism have been identified in rats as well.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 1","pages":"1-9"},"PeriodicalIF":2.2,"publicationDate":"2018-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2017.1404211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35321107","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 resveratrol treatment on graft revascularization after islet transplantation in streptozotocin-induced diabetic mice.","authors":"Eun-Mi Lee, Inwon Park, Ye-Jee Lee, Young-Hye You, Ji-Won Kim, Myung-Jun Kim, Yu-Bae Ahn, Pilhan Kim, Seung-Hyun Ko","doi":"10.1080/19382014.2017.1414764","DOIUrl":"10.1080/19382014.2017.1414764","url":null,"abstract":"<p><p>We evaluated the effect of resveratrol (RSV) on graft survival after islet transplantation (ITx) in diabetic mice. Isolated islets from Balb/c mice (200 IEQ) were transplanted under the kidney capsule of diabetic Balb/c mice. Vehicle or RSV (200 mg/kg/day, orally) was given for 14 days after ITx. Two more control groups [STZ-treated (No-ITx-Control) and STZ+RSV-treated (No-ITx-RSV) mice without ITx] were added. Glucose tolerance tests (GTT) was performed at 14 days after ITx. In vitro, isolated islets pretreated with vehicle or RSV (1 μM) were incubated in a hypoxic chamber (O₂ 1%, 1hr). Some of the ITx was performed in mouse insulin 1 gene promoter-green fluorescent protein (MIP-GFP) transgenic mice and analyzed using an in vivo imaging system. After 14 days of ITx, 2-hr glucose levels on GTT in the RSV-treated group were significantly lower than those of other control groups. But the glucose status was not improved in No-ITx mice with RSV. At day 3, the percentage of Ki-67/insulin co-stained cells in islet graft was significantly increased in the RSV-ITx group. Immunostaining with anti-insulin and anti-BS-1 antibodies revealed significantly higher insulin-stained area and vascular density in RSV-treated islet grafts. The mean vessel volume per islet graft measured by in vivo imaging was significantly higher in the RSV-treated group at day 3. In isolated islets cultured in hypoxic conditions, the cell death rate and oxidative stress were significantly attenuated with RSV pretreatment. Hypoxic treatment for isolated islets decreased the expression of SIRT-1 mRNA, and this attenuation was recovered by RSV pretreatment. Our data suggest that RSV treatment improved glycemic control, beta-cell proliferation, reduced oxidative stress, and enhanced islet revascularization and the outcome of ITx in diabetic mice.</p>","PeriodicalId":14671,"journal":{"name":"Islets","volume":"10 1","pages":"25-39"},"PeriodicalIF":2.2,"publicationDate":"2018-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800387/pdf/kisl-10-01-1414764.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35736824","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":"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⁺ T cells specific for IGRP_206-214; 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⁺ 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⁺ and CD8⁺ 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}

{"title":"Systematic review of islet cryopreservation.","authors":"Greg G Kojayan,&nbsp;Michael Alexander,&nbsp;David K Imagawa,&nbsp;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}

{"title":"Evidence of unrestrained beta-cell proliferation and neogenesis in a patient with hyperinsulinemic hypoglycemia after gastric bypass surgery.","authors":"Nidheesh Dadheech,&nbsp;Dominique Garrel,&nbsp;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}

{"title":"In vivo monitoring of intracellular Ca²⁺ dynamics in the pancreatic β-cells of zebrafish embryos.","authors":"Reka Lorincz,&nbsp;Christopher H Emfinger,&nbsp;Andrea Walcher,&nbsp;Michael Giolai,&nbsp;Claudia Krautgasser,&nbsp;Maria S Remedi,&nbsp;Colin G Nichols,&nbsp;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 Ca²⁺ sensor in pancreatic β-cells to monitor a key step in glucose induced insulin secretion; the elevations of intracellular [Ca²⁺]_i. In vivo and ex vivo analyses of [Ca²⁺]_i 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 [Ca²⁺]_i responses, while intravenous glucose injections cause immediate and islet-wide synchronized [Ca²⁺]_i fluctuations. Finally, we demonstrate that embryos with disrupted mutation of the Ca_V1.2 channel gene cacna1c are hyperglycemic and that this phenotype is associated with glucose-independent [Ca²⁺]_i 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 [Ca²⁺]_i 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":"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}