المؤلفون: Colli, Maikel L., Hill, Jessica L. E., Marroquí, Laura, Chaffey, Jessica, Dos Santos, Reinaldo S., Leete, Pia, Coomans de Brachène, Alexandra, Paula, Flavia M. M., Op de Beeck, Anne, Castela, Angela, Marselli, Lorella, Krogvold, Lars, Dahl-Jorgensen, Knut, Marchetti, Piero, Morgan, Noel G., Richardson, Sarah J., Eizirik, Décio L.

المساهمون: Colli, Maikel L., Hill, Jessica L. E., Marroquí, Laura, Chaffey, Jessica, Dos Santos, Reinaldo S., Leete, Pia, Coomans de Brachène, Alexandra, Paula, Flavia M. M., Op de Beeck, Anne, Castela, Angela, Marselli, Lorella, Krogvold, Lar, Dahl-Jorgensen, Knut, Marchetti, Piero, Morgan, Noel G., Richardson, Sarah J., Eizirik, Décio L.

مصطلحات موضوعية: CD274, Immune checkpoint inhibitor, IRF1, Pancreatic beta cell, Pancreatic islet, PDL-1, PDL1, Type 1 diabete, Adolescent, Adult, B7-H1 Antigen, Biomarker, Cell Line, Child, Preschool, Diabetes Mellitus, Type 1, Human, Insulin-Secreting Cell, Interferon Regulatory Factor-1, Interferon-alpha, Interferon-gamma, Islets of Langerhan, Middle Aged, Young Adult, Gene Expression Regulation, Biochemistry, Genetics and Molecular Biology (all)

الوصف: Background: Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated. Methods: The expression of PDL1, IRF1, insulin and glucagon was evaluated in samples of T1D donors by immunofluorescence. Cytokine-induced PDL1 expression in the human beta cell line, EndoC-βH1, and in primary human pancreatic islets was determined by real-time RT-PCR, flow cytometry and Western blot. Specific and previously validated small interference RNAs were used to inhibit STAT1, STAT2, IRF1 and JAK1 signaling. Key results were validated using the JAK inhibitor Ruxolitinib. Findings: PDL1 was present in insulin-positive cells from twelve T1D individuals (6 living and 6 deceased donors) but absent from insulin-deficient islets or from the islets of six non-diabetic controls. Interferons-α and -γ, but not interleukin-1β, induced PDL1 expression in vitro in human islet cells and EndoC-βH1 cells. Silencing of STAT1 or STAT2 individually did not prevent interferon-α-induced PDL1, while blocking of JAKs – a proposed therapeutic strategy for T1D – or IRF1 prevented PDL1 induction. Interpretation: These findings indicate that PDL1 is expressed in beta cells from people with T1D, possibly to attenuate the autoimmune assault, and that it is induced by both type I and II interferons via IRF1.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/30269996; info:eu-repo/semantics/altIdentifier/wos/WOS:000447685300041; volume:36; firstpage:367; lastpage:375; numberofpages:9; journal:EBIOMEDICINE; info:eu-repo/grantAgreement/EC/H2020/115797 667191; http://hdl.handle.net/11568/954955Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85054193057; https://www.sciencedirect.com/science/article/pii/S2352396418303980Test

الإتاحة: https://doi.org/10.1016/j.ebiom.2018.09.040Test
http://hdl.handle.net/11568/954955Test
https://www.sciencedirect.com/science/article/pii/S2352396418303980Test

المؤلفون: D'Addio F., Maestroni A., Assi E., Ben Nasr M., Amabile G., Usuelli V., Loretelli C., Bertuzzi F., Antonioli B., Cardarelli F., El Essawy B., Solini A., Gerling I. C., Bianchi C., Becchi G., Mazzucchelli S., Corradi D., Fadini G. P., Foschi D., Markmann J. F., Orsi E., Skrha J., Camboni M. G., Abdi R., James Shapiro A. M., Folli F., Ludvigsson J., Del Prato S., Zuccotti G., Fiorina P.

المساهمون: D'Addio, F., Maestroni, A., Assi, E., Ben Nasr, M., Amabile, G., Usuelli, V., Loretelli, C., Bertuzzi, F., Antonioli, B., Cardarelli, F., El Essawy, B., Solini, A., Gerling, I. C., Bianchi, C., Becchi, G., Mazzucchelli, S., Corradi, D., Fadini, G. P., Foschi, D., Markmann, J. F., Orsi, E., Skrha, J., Camboni, M. G., Abdi, R., James Shapiro, A. M., Folli, F., Ludvigsson, J., Del Prato, S., Zuccotti, G., Fiorina, P.

مصطلحات موضوعية: Adult, Animal, Cells, Cultured, Diabetes Mellitus, Type 1, Type 2, Female, Homeostasi, Human, Immunoblotting, Insulin-Like Growth Factor Binding Protein 3, Insulin-Secreting Cell, Male, Membrane Protein, Mice, Inbred C57BL, Inbred NOD, Knockout, Transgenic, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Gene Expression Regulation

الوصف: Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients’ cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/35115561; info:eu-repo/semantics/altIdentifier/wos/WOS:000752207900013; volume:13; issue:1; firstpage:684; journal:NATURE COMMUNICATIONS; http://hdl.handle.net/11568/1136917Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85124057555

الإتاحة: https://doi.org/10.1038/s41467-022-28360-2Test
http://hdl.handle.net/11568/1136917Test

المؤلفون: E. Muscelli, A. Casolaro, A. Gastaldelli, A. Mari, G. Seghieri, B. Astiarraga, Y. Chen, M. Alba, J. Holst, FERRANNINI, ELEUTERIO

المساهمون: E., Muscelli, A., Casolaro, A., Gastaldelli, A., Mari, G., Seghieri, B., Astiarraga, Y., Chen, M., Alba, J., Holst, Ferrannini, Eleuterio

مصطلحات موضوعية: Adult, Aged, Blood Glucose, analysis, Diabetes Mellitu, Type 2, blood/drug therapy/physiopathology, Double-Blind Method, Female, Glucagon, blood, Glucagon-Like Peptide 1, Humans, Hypoglycemic Agent, pharmacology/therapeutic use, Insulin-Secreting Cell, drug effects/physiology, Male, Middle Aged, Pyrazine, Triazole

الوصف: Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes. The underlying mechanisms (incretin effect, β-cell function, endogenous glucose production) are not well known.The aim of the study was to examine mechanisms of the antihyperglycemic effect of DPP-4 inhibitors.We administered a mixed meal with glucose tracers ([6,6-(2)H(2)]-glucose infused, [1-(2)H]-glucose ingested), and on a separate day, a glucose infusion matched the glucose responses to the meal (isoglycemic test) in 50 type 2 diabetes patients (hemoglobin A(1c) = 7.4 ± 0.8\%) and seven controls; 47 diabetic completers were restudied after 6 wk. Glucose fluxes were calculated, and β-cell function was assessed by mathematical modeling. The incretin effect was calculated as the ratio of oral to iv insulin secretion.We conducted a 6-wk, double-blind, randomized treatment with sitagliptin (100 mg/d; n = 25) or placebo (n = 22).Relative to placebo, meal-induced changes in fasting glucose and glucose area under the curve (AUC) were greater with sitagliptin, in parallel with a lower appearance of oral glucose [difference (post-pre) AUC = -353 ± 915 vs. +146 ± 601 μmol · kg(-1) · 5 h] and greater suppression of endogenous glucose production. Insulin sensitivity improved 10\%, whereas total insulin secretion was unchanged. During the meal, β-cell glucose sensitivity improved (+19[29] vs. 5[21] pmol · min(-1) · m(-2) · mm(-1); median [interquartile range]) and glucagon AUC decreased (19.6 ± 7.5 to 17.3 ± 7.1 ng · ml(-1) · 5 h), whereas intact glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 AUC increased with sitagliptin vs. placebo. The incretin effect was unchanged because sitagliptin increased β-cell glucose sensitivity also during the isoglycemic test.Chronic sitagliptin treatment improves glycemic control by lowering the appearance of oral glucose, postprandial endogenous glucose release, and glucagon response, and by improving insulin sensitivity and β-cell glucose sensing in response to ...

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/22685234; volume:97; firstpage:2818; lastpage:2826; numberofpages:8; journal:THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; http://hdl.handle.net/11568/231754Test; http://dx.doi.org/10.1210/jc.2012-1205Test

الإتاحة: https://doi.org/10.1210/jc.2012-1205Test
http://hdl.handle.net/11568/231754Test