IF 2.2 4区医学

Islets Pub Date : 2019-01-01 Epub Date: 2019-05-14 DOI: 10.1080/19382014.2019.1599708

Jung Hoon Cho, Kyeong-Min Lee, Yun-Il Lee, Hong Gil Nam, Won Bae Jeon

{"title":"Glutamate decarboxylase 67 contributes to compensatory insulin secretion in aged pancreatic islets.","authors":"Jung Hoon Cho, Kyeong-Min Lee, Yun-Il Lee, Hong Gil Nam, Won Bae Jeon","doi":"10.1080/19382014.2019.1599708","DOIUrl":"https://doi.org/10.1080/19382014.2019.1599708","url":null,"abstract":"Pancreatic islets play an essential role in regulating blood glucose levels. Age-dependent development of glucose intolerance and insulin resistance results in hyperglycemia, which in turn stimulates insulin synthesis and secretion from aged islets, to fulfill the increased demand for insulin. However, the mechanism underlying enhanced insulin secretion remains unknown. Glutamic acid decarboxylase 67 (GAD67) catalyzes the conversion of glutamate into γ-aminobutyric acid (GABA) and CO2. Both glutamate and GABA can affect islet function. Here, we investigated the role of GAD67 in insulin secretion in young (3 month old) and aged (24 month old) C57BL/6J male mice. Unlike young mice, aged mice displayed glucose-intolerance and insulin-resistance. However, aged mice secreted more insulin and showed lower fed blood glucose levels than young mice. GAD67 levels in primary islets increased with aging and in response to high glucose levels. Inhibition of GAD67 activity using a potent inhibitor of GAD, 3-mercaptopropionic acid, abrogated glucose-stimulated insulin secretion from a pancreatic β-cell line and from young and aged islets. Collectively, our results suggest that blood glucose levels regulate GAD67 expression, which contributes to β-cell responses to impaired glucose homeostasis caused by advanced aging.","PeriodicalId":14671,"journal":{"name":"Islets","volume":"11 2","pages":"33-43"},"PeriodicalIF":2.2,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2019.1599708","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37234662","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}

引用次数: 7

Use of anti-inflammatory agents in clinical islet cell transplants: A qualitative systematic analysis. 抗炎药在临床胰岛细胞移植中的应用:定性系统分析。

IF 2.2 4区医学

Islets Pub Date : 2019-01-01 DOI: 10.1080/19382014.2019.1601543

Kristen R Szempruch, Oyshik Banerjee, Rebecca C McCall, Chirag S Desai

引用次数: 22

RORB and RORC associate with human islet dysfunction and inhibit insulin secretion in INS-1 cells. RORB和RORC与胰岛功能障碍有关，并抑制INS-1细胞的胰岛素分泌。

IF 2.2 4区医学

Islets Pub Date : 2019-01-01 Epub Date: 2019-02-14 DOI: 10.1080/19382014.2019.1566684

Jalal Taneera, Abdul Khader Mohammed, Sarah Dhaiban, Mawieh Hamad, Rashmi B Prasad, Nabil Sulaiman, Albert Salehi

{"title":"RORB and RORC associate with human islet dysfunction and inhibit insulin secretion in INS-1 cells.","authors":"Jalal Taneera, Abdul Khader Mohammed, Sarah Dhaiban, Mawieh Hamad, Rashmi B Prasad, Nabil Sulaiman, Albert Salehi","doi":"10.1080/19382014.2019.1566684","DOIUrl":"https://doi.org/10.1080/19382014.2019.1566684","url":null,"abstract":"Little is known about the expression and function of Retinoic acid-related orphan receptors (RORA, B, and C) in pancreatic β cells. Here in, we utilized cDNA microarray and RNA sequencing approaches to investigate the expression pattern of ROR receptors in normal and diabetic human pancreatic islets. Possible correlations between RORs expression and HbA1c levels as well as insulin secretory capacity in isolated human islets were evaluated. The impact of RORB and RORC expression on insulin secretion in INS-1 (832/13) cells was validated as well. While RORA was the highest expressed gene among the three RORs in human islet cells, RORC was the highest expressed in INS-1 cells (832/13) and while RORB was the lowest expressed gene in human islet cells, RORA was the highest expressed in INS-1 cells (832/13). The expression of RORB and RORC was significantly lower in diabetic/hyperglycemic donors as compared with non-diabetic counterparts. Furthermore, while the expression of RORB correlated positively with insulin secretion and negatively with HbA1c, that of RORC correlated negatively with HbA1c. The expression pattern of RORA did not correlate with either of the two parameters. siRNA silencing of RORB or RORC in INS-1 (832/13) cells resulted in a significant downregulation of insulin mRNA expression and insulin secretion. These findings suggest that RORB and RORC are part of the molecular cascade that regulates insulin secretion in pancreatic β cells; and insight that provides for further work on the potential therapeutic utility of RORB and RORC genes in β cell dysfunction in type 2 diabetes.","PeriodicalId":14671,"journal":{"name":"Islets","volume":" ","pages":"10-20"},"PeriodicalIF":2.2,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2019.1566684","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40448338","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}

引用次数: 16

Palmitate is not an effective fuel for pancreatic islets and amplifies insulin secretion independent of calcium release from endoplasmic reticulum. 棕榈酸酯不是胰岛的有效燃料，它能增加独立于内质网钙释放的胰岛素分泌。

IF 2.2 4区医学

Islets Pub Date : 2019-01-01 Epub Date: 2019-05-14 DOI: 10.1080/19382014.2019.1601490

Iok Teng Kuok, Austin M Rountree, Seung-Ryoung Jung, Ian R Sweet

{"title":"Palmitate is not an effective fuel for pancreatic islets and amplifies insulin secretion independent of calcium release from endoplasmic reticulum.","authors":"Iok Teng Kuok, Austin M Rountree, Seung-Ryoung Jung, Ian R Sweet","doi":"10.1080/19382014.2019.1601490","DOIUrl":"https://doi.org/10.1080/19382014.2019.1601490","url":null,"abstract":"The aim of the study was to determine the acute contribution of fuel oxidation in mediating the increase in insulin secretion rate (ISR) in response to fatty acids. Measures of mitochondrial metabolism, as reflected by oxygen consumption rate (OCR) and cytochrome c reduction, calcium signaling, and ISR by rat islets were used to evaluate processes stimulated by acute exposure to palmitic acid (PA). The contribution of mitochondrial oxidation of PA was determined in the presence and absence of a blocker of mitochondrial transport of fatty acids (etomoxir) at different glucose concentrations. Subsequent to increasing glucose from 3 to 20 mM, PA caused small increases in OCR and cytosolic calcium (about 20% of the effect of glucose). In contrast, the effect of PA on ISR was almost 3 times that by glucose, suggesting that the metabolism of PA is not the dominant mechanism mediating PA's effect on ISR. This was further supported by lack of inhibition of PA-stimulated OCR and ISR when blocking entry of PA into mitochondria (with etomoxir), and PA's lack of stimulation of reduced cytochrome c in the presence of high glucose. Consistent with the lack of metabolic stimulation by PA, an inhibitor of calcium release from the endoplasmic reticulum, but not a blocker of L-type calcium channels, abolished the PA-induced elevation of cytosolic calcium. Notably, ISR was unaffected by thapsigargin showing the dissociation of endoplasmic reticulum calcium release and second phase insulin secretion. In conclusion, stimulation of ISR by PA was mediated by mechanisms largely independent of the oxidation of the fuel.","PeriodicalId":14671,"journal":{"name":"Islets","volume":"11 3","pages":"51-64"},"PeriodicalIF":2.2,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2019.1601490","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37234660","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}

引用次数: 9

Pancreatic beta cell/islet mass and body mass index. 胰腺细胞/胰岛质量和身体质量指数。

IF 2.2 4区医学

Islets Pub Date : 2019-01-01 Epub Date: 2019-01-22 DOI: 10.1080/19382014.2018.1557486

Michael P Dybala, Scott K Olehnik, Jonas L Fowler, Karolina Golab, J Michael Millis, Justyna Golebiewska, Piotr Bachul, Piotr Witkowski, Manami Hara

{"title":"Pancreatic beta cell/islet mass and body mass index.","authors":"Michael P Dybala, Scott K Olehnik, Jonas L Fowler, Karolina Golab, J Michael Millis, Justyna Golebiewska, Piotr Bachul, Piotr Witkowski, Manami Hara","doi":"10.1080/19382014.2018.1557486","DOIUrl":"https://doi.org/10.1080/19382014.2018.1557486","url":null,"abstract":"Body mass index (BMI) is widely used to define obesity. In studies of pancreatic beta-cell/islet mass, BMI is also a common standard for matching control subjects in comparative studies along with age and sex, based on the existing dogma of their significant positive correlation reported in the literature. We aimed to test the feasibility of BMI and BSA to assess obesity and predict beta-cell/islet mass. We used National Health and Nutrition Examination Survey (NHANES) data that provided dual-energy Xray absorptiometry (DXA)-measured fat mass (percent body fat; %BF), BMI, and BSA for adult subjects (20-75y; 4,879 males and 4,953 females). We then analyzed 152 cases of islet isolation performed at our center for correlation between islet yields and various donor anthropometric indices. From NHANES, over 50% of male subjects and 60% of female subjects with BMI:20.1-28.1 were obese as defined by %BF, indicating a poor correlation between BMI and %BF. BSA was also a poor indicator of %BF, as broad overlap was observed in different BSA ranges. Additionally, BMI and BSA ranges markedly varied between sex and race/ethnicity groups. From islet isolation, BMI and BSA accounted for only a small proportion of variance in islet equivalent (IEQ; r2 = 0.09 and 0.11, respectively). BMI and obesity were strongly correlated in cases of high BMI subjects. However, the critical populations were non-obese subjects with BMI ranging from 20.1-28.1, in which a substantial proportion of individuals may carry excess body fat. Correlations between BMI, BSA, pancreas weight and beta-cell/islet mass were low.","PeriodicalId":14671,"journal":{"name":"Islets","volume":"11 1","pages":"1-9"},"PeriodicalIF":2.2,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2018.1557486","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36884784","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}

引用次数: 12

Characterization of host defense molecules in the human pancreas. 人类胰腺中宿主防御分子的特征。

IF 1.9 4区医学

Islets Pub Date : 2019-01-01 Epub Date: 2019-06-26 DOI: 10.1080/19382014.2019.1585165

Anton Stenwall, Sofie Ingvast, Oskar Skog, Olle Korsgren

{"title":"Characterization of host defense molecules in the human pancreas.","authors":"Anton Stenwall, Sofie Ingvast, Oskar Skog, Olle Korsgren","doi":"10.1080/19382014.2019.1585165","DOIUrl":"10.1080/19382014.2019.1585165","url":null,"abstract":"The gut microbiota can play a role in pancreatitis and, likely, in the development of type 1 diabetes (T1D). Anti-microbial peptides and secretory proteins are important mediators of the innate immune response against bacteria but their expression in the human pancreas is not fully known. In this study, immunohistochemistry was used to analyze the expression of seven anti-microbial peptides (Defensin α1, α4, β1-4 and Cathelicidin) and two secretory proteins with known antimicrobial properties (REG3A and GP2) in pancreatic and duodenal biopsies from 10 non-diabetic organ donors and one organ donor that died at onset of T1D. Immunohistochemical data was compared with previously published whole-transcriptome data sets. Seven (Defensin α1, β2, β3, α4, GP2, Cathelicidin, and REG3A) host defense molecules showed positive staining patterns in most non-diabetic organ donors, whereas two (Defensin β1 and β4) were negative in all non-diabetic donors. Two molecules (Defensin α1 and GP2) were restricted to the exocrine pancreas whereas two (Defensin β3, α4) were only expressed in islet tissue. Cathelicidin, β2, and REG3A were expressed in both islets and exocrine tissue. The donor that died at onset of T1D had generally less positivity for the host defense molecules, but, notably, this pancreas was the only one where defensin β1 was found. Neither donor age, immune-cell infiltration, nor duodenal expression correlated to the pancreatic expression of host defense molecules. In conclusion, these findings could have important implications for the inflammatory processes in diabetes and pancreatitis as we find several host defense molecules expressed by the pancreatic tissue.","PeriodicalId":14671,"journal":{"name":"Islets","volume":"11 4","pages":"89-101"},"PeriodicalIF":1.9,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/92/d0/kisl-11-04-1585165.PMC6682263.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37367359","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}

引用次数: 0

Islet amyloidosis in a child with type 1 diabetes. 1型糖尿病儿童的胰岛淀粉样变。

IF 2.2 4区医学

Islets Pub Date : 2019-01-01 Epub Date: 2019-05-14 DOI: 10.1080/19382014.2019.1599707

Maria L Beery, Laura M Jacobsen, Mark A Atkinson, Alexandra E Butler, Martha Campbell-Thompson

{"title":"Islet amyloidosis in a child with type 1 diabetes.","authors":"Maria L Beery, Laura M Jacobsen, Mark A Atkinson, Alexandra E Butler, Martha Campbell-Thompson","doi":"10.1080/19382014.2019.1599707","DOIUrl":"https://doi.org/10.1080/19382014.2019.1599707","url":null,"abstract":"Histopathology based studies of the pancreas obtained from organ donors are increasing our awareness of islet phenotypic heterogeneity during development and aging, as well as in settings of type 1 diabetes, type 2 diabetes, monogenic diabetes or other forms of this metabolic disease. Islet amyloidosis represents a histopathological feature classically ascribed to patients with type 2 diabetes. Herein, the occurrence of islet amyloidosis and its severity are reported in a child with type 1 diabetes along with histological comparisons of islet amyloidosis in two young adults with recent-onset type 1 diabetes. Islet amyloidosis was infrequent yet widely distributed throughout the pancreas in the child with type 1 diabetes and both adults with type 1 diabetes, with no such pathology seen in matched control donors. Analysis of these cases add to the increasing appreciation of islet heterogeneity in children and young adults with type 1 diabetes. Such knowledge also supports a notion that multiple pathophysiological mechanisms underlie the loss of functional β-cell mass in the spectrum of clinical phenotypes in patients with type 1 diabetes.","PeriodicalId":14671,"journal":{"name":"Islets","volume":"11 2","pages":"44-49"},"PeriodicalIF":2.2,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2019.1599707","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37234749","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}

引用次数: 15

Mechanisms of octanoic acid potentiation of insulin secretion in isolated islets. 辛酸增强离体胰岛胰岛素分泌的机制。

IF 2.2 4区医学

Islets Pub Date : 2019-01-01 Epub Date: 2019-03-08 DOI: 10.1080/19382014.2019.1566683

Tingting Zhang, Pan Chen, Charles A Stanley, Toshinori Hoshi, Changhong Li

{"title":"Mechanisms of octanoic acid potentiation of insulin secretion in isolated islets.","authors":"Tingting Zhang, Pan Chen, Charles A Stanley, Toshinori Hoshi, Changhong Li","doi":"10.1080/19382014.2019.1566683","DOIUrl":"https://doi.org/10.1080/19382014.2019.1566683","url":null,"abstract":"A potentiating effect of medium-chain triglycerides on glucose-stimulated insulin secretion (GSIS) has been observed since the 1960s. Subsequent observations identified octanoic acid (OA), the main component of medium-chain triglyceride, as the potentiator of GSIS, but the mechanism was unclear. We used wild-type (WT), short-chain 3-hydroxyacyl-CoA dehydrogenase knockout (Hadh-/-), and sulfonylurea receptor 1 knockout (Sur1-/-) mouse islets to define the mechanism of OA potentiation of insulin secretion. Application of OA alone induced a 2- to 3- fold increase of insulin secretion with an apparent threshold of 3 mM in WT mouse islets, suggesting that OA itself is a weak insulin secretagogue. However, OA at 1 mM strongly potentiated fuel-stimulated insulin secretion, especially GSIS. The potentiating effect on fuel-stimulated insulin secretion by OA did not require fatty acid β-oxidation because OA also potentiated amino acid-stimulated insulin secretion in islets isolated from Hadh-/- mice, which cannot fully oxidize OA. Measurements using Sur1-/- islets indicated that the potentiating effect of OA on fuel-stimulated insulin secretion is Ca2+ dependent and is often accompanied by β-cell membrane potential depolarization, and may also involve the Ca2+/calmodulin complex. Experiments using DCPIB, an ethacrynic acid derivative, to inhibit volume-sensitive anion channels (VSACs) in Sur1-/- islets demonstrated that the potentiation effects of OA on insulin secretion are in part medicated by activation of VSAC. In addition, inhibition of IP3 receptor also abolishes the OA-induced intracellular Ca2+ increase in Sur1-/- islets.","PeriodicalId":14671,"journal":{"name":"Islets","volume":"11 4","pages":"77-88"},"PeriodicalIF":2.2,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2019.1566683","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37038266","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}

引用次数: 5

Class IIa HDACs do not influence beta-cell function under normal or high glucose conditions. 在正常或高葡萄糖条件下，IIa类hdac不影响β细胞功能。

IF 2.2 4区医学

Islets Pub Date : 2019-01-01 Epub Date: 2019-05-21 DOI: 10.1080/19382014.2019.1617621

Jacob McCann, Megan Ellis, Sean L McGee, Kathryn Aston-Mourney

{"title":"Class IIa HDACs do not influence beta-cell function under normal or high glucose conditions.","authors":"Jacob McCann, Megan Ellis, Sean L McGee, Kathryn Aston-Mourney","doi":"10.1080/19382014.2019.1617621","DOIUrl":"https://doi.org/10.1080/19382014.2019.1617621","url":null,"abstract":"Inhibiting Class IIa Histone Deacetylase (HDAC) function is a promising approach to therapeutically enhance skeletal and cardiac muscle metabolic health in several chronic diseases including type 2 diabetes. However, the importance of Class IIa HDACs in the beta-cell remains unknown. As beta-cell function is vital to maintaining glycaemia it is essential that the importance of Class IIa HDACs in the beta-cell is determined. Here we used the INS-1E cell line cultured in normal glucose (11.1 mM) or hyperglycaemic (20 mM) conditions for 48 hrs to represent cells in a normal and diabetic environment respectively. Cells cultured in high glucose showed significantly reduced insulin secretory function and increased apoptotic signalling compared to cells cultured in normal glucose. Class IIa HDACS, HDAC-4 and -5, were not regulated at the transcript or protein level under normal or hyperglycaemic conditions suggesting that they may not play a role in beta-cell dysfunction. Furthermore, overexpression of wild-type HDAC-4 and -5 or dominant negative HDAC-4 and -5 did not alter insulin secretion, insulin mRNA expression or apoptotic signalling under normal or hyperglycaemic conditions. This suggests that Class IIa Histone Deacetylases do not play an important physiological role in the beta-cell under normal or diabetic conditions. Thus, Class IIa Histone Deacetylase inhibitors are not likely to have a detrimental effect on beta-cells supporting the use of these inhibitors to treat metabolic diseases such as type 2 diabetes.","PeriodicalId":14671,"journal":{"name":"Islets","volume":"11 5","pages":"112-118"},"PeriodicalIF":2.2,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/19382014.2019.1617621","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37263284","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}

引用次数: 3

Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation. 胰岛素作为一种抑制因子，抑制了 PAR2 诱导胰岛细胞转分化的能力。

IF 1.9 4区医学

Islets Pub Date : 2018-09-19 DOI: 10.1080/19382014.2018.1472839

Seung-Hee Lee, Ergeng Hao, David Scharp, Fred Levine

{"title":"Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation.","authors":"Seung-Hee Lee, Ergeng Hao, David Scharp, Fred Levine","doi":"10.1080/19382014.2018.1472839","DOIUrl":"10.1080/19382014.2018.1472839","url":null,"abstract":"Recently, we showed that pancreatitis in the context of profound β-cell deficiency was sufficient to induce islet cell transdifferentiation. In some circumstances, this effect was sufficient to result in recovery from severe diabetes. More recently, we showed that the molecular mechanism by which pancreatitis induced β-cell neogenesis by transdifferentiation was activation of an atypical GPCR called Protease-Activated Receptor 2 (PAR2). However, the ability of PAR2 to induce transdifferentiation occurred only in the setting of profound β-cell deficiency, implying the existence of a repressive factor from those cells. Here we show that the repressor from β-cells is insulin. Treatment of primary islets with a PAR2 agonist (2fLI) in combination with inhibitors of insulin secretion and signaling was sufficient to induce insulin and PAX4 gene expression. Moreover, in primary human islets, this treatment also led to the induction of bihormonal islet cells coexpressing glucagon and insulin, a hallmark of islet cell transdifferentiation. Mechanistically, insulin inhibited the positive effect of a PAR2 agonist on insulin gene expression and also led to an increase in PAX4, which plays an important role in islet cell transdifferentiation. The studies presented here demonstrate that insulin represses transdifferentiation of α- to β-cells induced by activation of PAR2. This provides a mechanistic explanation for the observation that α- to β-cell transdifferentiation occurs only in the setting of severe β-cell ablation. The mechanistic understanding of islet cell transdifferentiation and the ability to modulate that process using available pharmacological reagents represents an important step along the path towards harnessing this novel mechanism of β-cell neogenesis as a therapy for diabetes.","PeriodicalId":14671,"journal":{"name":"Islets","volume":" ","pages":"201-212"},"PeriodicalIF":1.9,"publicationDate":"2018-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300087/pdf/kisl-10-06-1472839.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36066918","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}

引用次数: 0

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