{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T20:14:41Z","timestamp":1790540081965,"version":"4.1.0"},"reference-count":83,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T00:00:00Z","timestamp":1582070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is an outer mitochondria membrane protein that serves as a mitochondrial gatekeeper, controlling metabolic and energy homeostasis, as well as crosstalk between the mitochondria and the rest of the cell. It is also involved in mitochondria-mediated apoptosis. Here, we demonstrate that the VDAC1-based peptide, R-Tf-D-LP4, affects several parameters of a NAFLD mouse model in which administration of streptozotocin (STZ) and high-fat diet 32 (STZ\/HFD-32) led to both type 2 diabetes (T2D) and NAFLD phenotypes. We focused on diabetes, showing that R-Tf-D-LP4 peptide treatment of STZ\/HFD-32 fed mice restored the elevated blood glucose back to close to normal levels, and increased the number and average size of islets and their insulin content as compared to untreated controls. Similar results were obtained when staining the islets for glucose transporter type 2. In addition, the R-Tf-D-LP4 peptide decreased the elevated glucose levels in a mouse displaying obese, diabetic, and metabolic symptoms due to a mutation in the obese (ob) gene. To explore the cause of the peptide-induced improvement in the endocrine pancreas phenotype, we analyzed the expression levels of the proliferation marker, Ki-67, and found it to be increased in the islets of STZ\/HFD-32 fed mice treated with the R-Tf-D-LP4 peptide. Moreover, peptide treatment of STZ\/HFD-32 fed mice caused an increase in the expression of \u03b2-cell maturation and differentiation PDX1 transcription factor that enhances the expression of the insulin-encoding gene, and is essential for islet development, function, proliferation, and maintenance of glucose homeostasis in the pancreas. This increase occurred mainly in the \u03b2-cells, suggesting that the source of their increased number after R-Tf-D-LP4 peptide treatment was most likely due to \u03b2-cell proliferation. These results suggest that the VDAC1-based R-Tf-D-LP4 peptide has potential as a treatment for diabetes.<\/jats:p>","DOI":"10.3390\/cells9020481","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T04:21:26Z","timestamp":1582604486000},"page":"481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-1320","authenticated-orcid":false,"given":"Srinivas","family":"Pittala","sequence":"first","affiliation":[{"name":"Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idan","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumasree","family":"De","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4207-9453","authenticated-orcid":false,"given":"Swaroop","family":"Kumar Pandey","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataly","family":"Melnikov","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tehila","family":"Hyman","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6756-4340","authenticated-orcid":false,"given":"Varda","family":"Shoshan-Barmatz","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.mito.2011.04.001","article-title":"VDAC, a multi-functional mitochondrial protein as a pharmacological target","volume":"12","year":"2012","journal-title":"Mitochondrion"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1016\/j.bbamem.2014.10.040","article-title":"The mitochondrial voltage-dependent anion channel 1 in tumor cells","volume":"1848","author":"Admoni","year":"2015","journal-title":"Biochim. Et. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.mam.2010.03.002","article-title":"VDAC, a multi-functional mitochondrial protein regulating cell life and death","volume":"31","author":"Zweckstetter","year":"2010","journal-title":"Mol. Aspects Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fonc.2017.00154","article-title":"Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics","volume":"7","author":"Krelin","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.15698\/cst2017.10.104","article-title":"VDAC1 at the crossroads of cell metabolism, apoptosis and cell stress","volume":"1","author":"Maldonado","year":"2017","journal-title":"Cell Stress"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1074\/jbc.M111.268920","article-title":"Structure-based analysis of VDAC1 protein: Defining oligomer contact sites","volume":"287","author":"Geula","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5698","DOI":"10.1128\/MCB.00165-10","article-title":"Oligomerization of the mitochondrial protein voltage-dependent anion channel is coupled to the induction of apoptosis","volume":"30","author":"Keinan","year":"2010","journal-title":"Mol. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1042\/BJ20041356","article-title":"Oligomeric states of the voltage-dependent anion channel and cytochrome c release from mitochondria","volume":"386","author":"Zalk","year":"2005","journal-title":"Biochem. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/B978-0-12-386931-9.00011-8","article-title":"Oligomerization of the mitochondrial protein VDAC1: From structure to function and cancer therapy","volume":"117","author":"Mizrachi","year":"2013","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1242\/jcs.040188","article-title":"The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins","volume":"122","author":"Arbel","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.2174\/138161206777585111","article-title":"The voltage-dependent anion channel (VDAC): Function in intracellular signalling, cell life and cell death","volume":"12","author":"Israelson","year":"2006","journal-title":"Curr. Pharm. Des."},{"key":"ref_12","first-page":"164","article-title":"VDAC1: From structure to cancer therapy","volume":"2","author":"Mizrachi","year":"2012","journal-title":"Front. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ko, J.H., Gu, W., Lim, I., Zhou, T., and Bang, H. (2014). Expression profiling of mitochondrial voltage-dependent anion channel-1 associated genes predicts recurrence-free survival in human carcinomas. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110094"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1016\/j.febslet.2010.02.049","article-title":"Voltage-dependent anion-selective channel (VDAC) in the plasma membrane","volume":"584","author":"Messina","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0014-5793(96)00442-5","article-title":"VDAC\/porin is present in sarcoplasmic reticulum from skeletal muscle","volume":"386","author":"Hadad","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6053","DOI":"10.1074\/jbc.M109.082990","article-title":"Voltage-dependent anion channel 1-based peptides interact with Bcl-2 to prevent antiapoptotic activity","volume":"285","author":"Arbel","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3946","DOI":"10.1074\/jbc.M803614200","article-title":"Voltage-dependent anion channel 1-based peptides interact with hexokinase to prevent its anti-apoptotic activity","volume":"284","author":"Arzoine","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e809","DOI":"10.1038\/cddis.2013.316","article-title":"VDAC1-based peptides: Novel pro-apoptotic agents and potential therapeutics for B-cell chronic lymphocytic leukemia","volume":"4","author":"Prezma","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23152","DOI":"10.1074\/jbc.M112.345918","article-title":"Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein","volume":"287","author":"Arbel","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"31329","DOI":"10.18632\/oncotarget.15455","article-title":"Mitochondrial VDAC1-based peptides: Attacking oncogenic properties in glioblastoma","volume":"8","author":"Arif","year":"2017","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.neo.2018.02.012","article-title":"Targeting Liver Cancer and Associated Pathologies in Mice with a Mitochondrial VDAC1-Based Peptide","volume":"20","author":"Pittala","year":"2018","journal-title":"Neoplasia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1002\/1878-0261.12313","article-title":"Selective induction of cancer cell death by VDAC1-based peptides and their potential use in cancer therapy","volume":"12","author":"Amsalem","year":"2018","journal-title":"Mol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pittala, S., Krelin, Y., Kuperman, Y., and Shoshan-Barmatz, V. (2019). A Mitochondrial VDAC1-Based Peptide Greatly Suppresses Steatosis and NASH-Associated Pathologies in a Mouse Model. Mol. Ther.","DOI":"10.1016\/j.ymthe.2019.06.017"},{"key":"ref_24","first-page":"5.47.1","article-title":"Streptozotocin-Induced Diabetic Models in Mice and Rats","volume":"70","author":"Furman","year":"2015","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1478-3231.2008.01718.x","article-title":"Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus","volume":"29","author":"Leite","year":"2009","journal-title":"Liver Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/ajg.2009.67","article-title":"NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: An eleven-year follow-up study","volume":"104","author":"Adams","year":"2009","journal-title":"Am. J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.2337\/dc07-0792","article-title":"Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men","volume":"30","author":"Shibata","year":"2007","journal-title":"Diabetes Care"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1159\/000282080","article-title":"Epidemiology of non-alcoholic fatty liver disease","volume":"28","author":"Bellentani","year":"2010","journal-title":"Dig. Dis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S81","DOI":"10.2337\/dc14-S081","article-title":"Diagnosis and classification of diabetes mellitus","volume":"37","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"850","DOI":"10.4239\/wjd.v6.i6.850","article-title":"Diabetes mellitus: The epidemic of the century","volume":"6","author":"Kharroubi","year":"2015","journal-title":"World J. Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1083\/jcb.201802095","article-title":"The cell biology of systemic insulin function","volume":"217","author":"Tokarz","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/S0140-6736(06)68341-4","article-title":"Type 1 diabetes","volume":"367","author":"Daneman","year":"2006","journal-title":"Lancet"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1136\/bmj.328.7442.750","article-title":"Type 1 diabetes: Recent developments","volume":"328","author":"Devendra","year":"2004","journal-title":"BMJ"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1002\/hep.25772","article-title":"Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis","volume":"56","author":"Loomba","year":"2012","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jhepr.2019.07.002","article-title":"From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options","volume":"1","author":"Gastaldelli","year":"2019","journal-title":"JHEP Reports"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8713","DOI":"10.3390\/ijms15058713","article-title":"Role of mitochondria in nonalcoholic fatty liver disease","volume":"15","author":"Nassir","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"854","DOI":"10.3109\/10715762.2013.830717","article-title":"Mitochondrial dysfunction in non-alcoholic fatty liver disease and insulin resistance: Cause or consequence?","volume":"47","author":"Baulies","year":"2013","journal-title":"Free Radical Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1089\/ars.2009.2531","article-title":"Mitochondrial dysfunction in diabetes: From molecular mechanisms to functional significance and therapeutic opportunities","volume":"12","author":"Sivitz","year":"2010","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.metabol.2009.07.009","article-title":"Skeletal muscle insulin resistance: The interplay of local lipid excess and mitochondrial dysfunction","volume":"59","author":"Chow","year":"2010","journal-title":"Metabolism"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.biocel.2017.12.019","article-title":"Mitochondria in non-alcoholic fatty liver disease","volume":"95","author":"Simoes","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.cmet.2018.09.008","article-title":"Preserving Insulin Secretion in Diabetes by Inhibiting VDAC1 Overexpression and Surface Translocation in beta Cells","volume":"29","author":"Zhang","year":"2019","journal-title":"Cell Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24986","DOI":"10.1074\/jbc.M116.744284","article-title":"Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction","volume":"291","author":"Shalev","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00795-013-0016-1","article-title":"A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma","volume":"46","author":"Fujii","year":"2013","journal-title":"Med. Mol. Morphol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1210\/endo.139.3.5823","article-title":"Glucose homeostasis in the nonobese diabetic mouse at the prediabetic stage","volume":"139","author":"Amrani","year":"1998","journal-title":"Endocrinology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1111\/j.1476-5381.2012.01911.x","article-title":"The use of animal models in diabetes research","volume":"166","author":"King","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1100\/tsw.2007.117","article-title":"The physiology of obese-hyperglycemic mice [ob\/ob mice]","volume":"7","author":"Lindstrom","year":"2007","journal-title":"Sci. World J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.2337\/diabetes.52.7.1716","article-title":"Increased islet volume but unchanged islet number in ob\/ob mice","volume":"52","author":"Bock","year":"2003","journal-title":"Diabetes"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1146\/annurev.nutr.28.061807.155518","article-title":"Sugar absorption in the intestine: The role of GLUT2","volume":"28","author":"Kellett","year":"2008","journal-title":"Annu. Rev. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"766","DOI":"10.2337\/diab.41.6.766","article-title":"Colocalization of GLUT2 glucose transporter, sodium\/glucose cotransporter, and gamma-glutamyl transpeptidase in rat kidney with double-peroxidase immunocytochemistry","volume":"41","author":"Cramer","year":"1992","journal-title":"Diabetes"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/ng.520","article-title":"New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk","volume":"42","author":"Dupuis","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0303-7207(97)00190-1","article-title":"The loss of GLUT2 expression in the pancreatic beta-cells of diabetic db\/db mice is associated with an impaired DNA-binding activity of islet-specific trans-acting factors","volume":"135","author":"Bonny","year":"1997","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/S1386-6346(01)00172-3","article-title":"Enhanced GLUT2 gene expression in an oleic acid-induced in vitro fatty liver model","volume":"23","author":"Okamoto","year":"2002","journal-title":"Hepatol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/ng1197-327","article-title":"Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2","volume":"17","author":"Guillam","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Stolarczyk, E., Le Gall, M., Even, P., Houllier, A., Serradas, P., Brot-Laroche, E., and Leturque, A. (2007). Loss of sugar detection by GLUT2 affects glucose homeostasis in mice. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0001288"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4251","DOI":"10.1002\/j.1460-2075.1993.tb06109.x","article-title":"IPF1, a homeodomain-containing transactivator of the insulin gene","volume":"12","author":"Ohlsson","year":"1993","journal-title":"EMBO J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"372","DOI":"10.2337\/dc17-1902","article-title":"Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis","volume":"41","author":"Mantovani","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1126\/science.aaa0672","article-title":"Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats","volume":"347","author":"Perry","year":"2015","journal-title":"Science"},{"key":"ref_60","first-page":"19","article-title":"Insulin and insulin resistance","volume":"26","author":"Wilcox","year":"2005","journal-title":"Clin. Biochem. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"135","DOI":"10.4161\/isl.2.3.11815","article-title":"Pancreatic islet plasticity: Interspecies comparison of islet architecture and composition","volume":"2","author":"Steiner","year":"2010","journal-title":"Islets"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/(SICI)1097-0029(19981115)43:4<332::AID-JEMT7>3.0.CO;2-1","article-title":"Transdifferentiation versus stem cell hypothesis for the regeneration of islet beta-cells in the pancreas","volume":"43","author":"Bouwens","year":"1998","journal-title":"Microsc. Res. Tech."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/MED.0000000000000042","article-title":"Human beta-cell regeneration: Progress, hurdles, and controversy","volume":"21","author":"Jurczyk","year":"2014","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/MED.0000000000000174","article-title":"Pancreatic islet cell development and regeneration","volume":"22","author":"Romer","year":"2015","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"188","DOI":"10.4161\/isl.20500","article-title":"alpha-cell role in beta-cell generation and regeneration","volume":"4","author":"Habener","year":"2012","journal-title":"Islets"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/BF00262208","article-title":"The life story of the pancreatic B cell","volume":"26","author":"Hellerstrom","year":"1984","journal-title":"Diabetologia"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0925-4773(02)00333-7","article-title":"Gene expression cascades in pancreatic development","volume":"120","author":"Wilson","year":"2003","journal-title":"Mech. Dev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11225","DOI":"10.1074\/jbc.M111272200","article-title":"Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion","volume":"277","author":"Brissova","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1101\/gad.12.12.1763","article-title":"beta-cell-specific inactivation of the mouse Ipf1\/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes","volume":"12","author":"Ahlgren","year":"1998","journal-title":"Genes Dev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ymgme.2007.06.008","article-title":"A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis","volume":"92","author":"Babu","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1210\/me.2011-1231","article-title":"Research resource: The pdx1 cistrome of pancreatic islets","volume":"26","author":"Khoo","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"ref_72","first-page":"2316","article-title":"Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1","volume":"118","author":"Park","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"19090","DOI":"10.1073\/pnas.0904849106","article-title":"Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress","volume":"106","author":"Sachdeva","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1073\/pnas.89.8.3170","article-title":"Isolation of the mitochondrial benzodiazepine receptor: Association with the voltage-dependent anion channel and the adenine nucleotide carrier","volume":"89","author":"McEnery","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1210\/me.2004-0307","article-title":"Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into leydig cell mitochondria","volume":"19","author":"Hauet","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0074-7742(02)51012-6","article-title":"Diabetes mellitus and the central nervous system","volume":"51","author":"McCall","year":"2002","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S1474-4422(08)70021-8","article-title":"Cognition and diabetes: A lifespan perspective","volume":"7","author":"Biessels","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1210\/er.2007-0034","article-title":"Cognitive dysfunction and diabetes mellitus","volume":"29","author":"Kodl","year":"2008","journal-title":"Endocr. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/S0074-7742(02)51013-8","article-title":"Diabetes, the brain, and behavior: Is there a biological mechanism underlying the association between diabetes and depression?","volume":"51","author":"Jacobson","year":"2002","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.neuint.2012.02.025","article-title":"LXR and TSPO as new therapeutic targets to increase the levels of neuroactive steroids in the central nervous system of diabetic animals","volume":"60","author":"Mitro","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.bcp.2015.06.020","article-title":"Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis","volume":"97","author":"Li","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.neuroscience.2009.08.005","article-title":"Neuroprotective effects of a ligand of translocator protein-18 kDa (Ro5-4864) in experimental diabetic neuropathy","volume":"164","author":"Giatti","year":"2009","journal-title":"Neuroscience"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"37345","DOI":"10.1038\/srep37345","article-title":"The antidepressant-like activity of AC-5216, a ligand for 18KDa translocator protein (TSPO), in an animal model of diabetes mellitus","volume":"6","author":"Qiu","year":"2016","journal-title":"Sci. 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