Cited by 669Pancreatic function and diabetesDiabetes Treatment and ManagementDiabetes and associated disorders

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Glucagon-Like Peptide 1 Inhibits Cell Apoptosis and Improves Glucose Responsiveness of Freshly Isolated Human Islets

Farilla, Loredana, Bulotta, Angela, Hirshberg, Boaz, Li Calzi, Sergio, Khoury, Nasif, Noushmehr, Houtan, Bertolotto, Cristina, Di Mario, Umberto, Harlan, David M., Perfetti, Riccardo·2003·Endocrinology

DOI 10.1210/en.2003-0323

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Abstract

The peptide hormone, glucagon-like peptide 1 (GLP-1), has been shown to increase glucose-dependent insulin secretion, enhance insulin gene transcription, expand islet cell mass, and inhibit beta-cell apoptosis in animal models of diabetes. The aim of the present study was to evaluate whether GLP-1 could improve function and inhibit apoptosis in freshly isolated human islets. Human islets were cultured for 5 d in the presence, or absence, of GLP-1 (10 nm, added every 12 h) and studied for viability and expression of proapoptotic (caspase-3) and antiapoptotic factors (bcl-2) as well as glucose-dependent insulin production. We observed better-preserved three-dimensional islet morphology in the GLP-1-treated islets, compared with controls. Nuclear condensation, a feature of cell apoptosis, was inhibited by GLP-1. The reduction in the number of apoptotic cells in GLP-1-treated islets was particularly evident at d 3 (6.1% apoptotic nuclei in treated cultures vs. 15.5% in controls; P < 0.01) and at d 5 (8.9 vs. 18.9%; P < 0.01). The antiapoptotic effect of GLP-1 was associated with the down-regulation of active caspase-3 (P < 0.001) and the up-regulation of bcl-2 (P < 0.01). The effect of GLP-1 on the intracellular levels of bcl-2 and caspase-3 was observed at the mRNA and protein levels. Intracellular insulin content was markedly enhanced in islets cultured with GLP-1 vs. control (P < 0.001, at d 5), and there was a parallel GLP-1-dependent potentiation of glucose-dependent insulin secretion (P < 0.01 at d 3; P < 0.05 at d 5). Our findings provide evidence that GLP-1 added to freshly isolated human islets preserves morphology and function and inhibits cell apoptosis.

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Background
Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell Apoptosis
Li, Y., Hansotia, T., Yusta, B., Ris, F., Halban, P. A., & Drucker, D. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209423200 · Cited by 589
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Self-citation
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Background
American College of Endocrinology Pre-Diabetes Consensus Conference: Part Two
Bloomgarden, Z. T. (2008) · Diabetes Care · doi:10.2337/dc08-zb11 · Cited by 26
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Background
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Background
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Chaudhry, S., Bernardes, M., Harris, P. E., & Maffei, A. (2016) · PubMed · Cited by 27
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Background
Multifaceted Therapeutic Approaches for a Multigenic Disease
Bottino, R., & Trucco, M. (2005) · Diabetes · doi:10.2337/diabetes.54.suppl_2.s79 · Cited by 27
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van Genugten, R. E., van Raalte, D. H., & Diamant, M. (2009) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(09)70006-3 · Cited by 26
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Phuwamongkolwiwat, P., Hira, T., & Hara, H. (2014) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201300871 · Cited by 26
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“In static incubation experiments with freshly isolated human islets, GLP-1 reduces spontaneous beta-cell apoptosis, improves glucose-stimulated insulin secretion and protects from gluco-lipotoxicity (115, 116).”
Background
Gene Therapy Progress and Prospects: Gene therapy for diabetes mellitus
Yechoor, V. K., & Chan, L. (2004) · Gene Therapy · doi:10.1038/sj.gt.3302412 · Cited by 26
Modulation of the Gastrointestinal Microbiome with Nondigestible Fermentable Carbohydrates To Improve Human Health
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“…by activating the transducer of regulated cAMP response element-binding protein (CREB) (TORC2) and the expression of the CREB and insulin receptor substrate 2 genes [57] Additionally, by boosting bcl-2 activity and blocking the proapoptotic Bax, activated CREB also supports beta cell survival [58].”
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Mize, D. L. E., & Salehi, M. (2013) · Current Diabetes Reports · doi:10.1007/s11892-013-0377-9 · Cited by 24
Pharmacological Actions of Glucagon-Like Peptide-1, Gastric Inhibitory Polypeptide, and Glucagon
Sekar, R., Singh, K., Arokiaraj, A. W. R., & Chow, B. (2016) · International review of cytology · doi:10.1016/bs.ircmb.2016.05.002 · Cited by 26
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Xie, Y., Wang, S., Wei-wei, S. H. A., Zhou, X., Wang, W., Li-pin, H. A. N., Li, D., & Demin, Y. (2008) · Chinese Medical Journal · doi:10.1097/00029330-200811010-00005 · Cited by 24
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Vilsbøll, T., Holst, J. J., & Knop, F. K. (2009) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2009.03.011 · Cited by 23
Sitagliptin: A novel agent for the management of type 2 diabetes mellitus
Pham, D. Q., Nogid, A., & Plakogiannis, R. (2008) · American Journal of Health-System Pharmacy · doi:10.2146/ajhp070248 · Cited by 25
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“Preclinical studies suggest that incretins play a role in the maintenance of normal β -cell mass and function by promoting β -cell neogenesis and decreasing apoptosis [14,15] .”
Background
The enteroinsular axis may mediate the diabetogenic effects of TCF7L2 polymorphisms
Nauck, M. A., & Meier, J. J. (2007) · Diabetologia · doi:10.1007/s00125-007-0832-8 · Cited by 24
“GLP-1 also increases the insulin content of beta cells [27, 28] and increases the functional performance of beta cells even in patients with type 2 diabetes [29, 30].”
Background
GLP-1 receptor agonist attenuates endoplasmic reticulum stress-mediated β-cell damage in Akita mice
Yamane, S., Hamamoto, Y., Harashima, S., Harada, N., Hamasaki, A., Toyoda, K., Fujita, K., Joo, E., Seino, Y., & Inagaki, N. (2010) · Journal of Diabetes Investigation · doi:10.1111/j.2040-1124.2010.00075.x · Cited by 22
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Giugliano, D., Standl, E., Vilsbøll, T., Betteridge, J. D., Bonadonna, R. C., Campbell, I. W., Schernthaner, G.-H., Staels, B., Trichopoulou, A., & Farinaro, E. (2009) · Acta Diabetologica · doi:10.1007/s00592-009-0134-3 · Cited by 23
“Additional effects or consequences of these drugs remain to be fully elucidated—more information would be useful relating to glucose control mechanisms (possible peripheral, hepatic or central action), the possibility of beta-cell protection (in vitro studies have shown that GLP-1 can preserve morphology and function,…”
Background
Effects of the glucagon-like peptide-1 (GLP-1) analogues exenatide, exenatide extended-release, and of the dipeptidylpeptidase-4 (DPP-4) inhibitor sitagliptin on glucose metabolism in healthy cats
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“Gastrointestinal symptoms are dose-320 dependent and gradual dose increase can be used to lessen symptoms (Fineman et al., 2004).”
Background
Incretin-based therapies: new treatments for type 2 diabetes in the new millennium
Horowitz, M. (2009) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s4975 · Cited by 23
“…insulin gene transcription and other steps in insulin biosynthesis, 37 and, in in vitro studies, has a trophic effect on β ‑cells by increasing proliferation and neogenesis, and inhibiting apoptosis, 38,39 which has the potential to retard or reverse β ‑cell failure, the fundamental defect in T2DM.”
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“GLP-1 does this by inhibiting CASP-3 activity (Wang and Brubaker, 2002); bcl-2 expression is upregulated, whereas Bax expression is downregulated (Farilla et al. 2003).”
Background
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Heckmann, N. D., Palmer, R. C., Mayfield, C. K., Gucev, G., Lieberman, J. R., & Hong, K. M. (2024) · Arthroplasty Today · doi:10.1016/j.artd.2024.101327 · Cited by 22
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Sjöholm, Å. (2009) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2009.01074.x · Cited by 22
GLP-1 receptor agonists today
Marre, M., & Penfornis, A. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.01.004 · Cited by 22
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Kini, S. U., Herron, D. M., & Yanagisawa, R. T. (2007) · Medical Clinics of North America · doi:10.1016/j.mcna.2007.06.007 · Cited by 22
“GLP-1 is an incretin that stimulates insulin secretion in response to enteric nutrients [ 34 ].”
Background
Sitagliptin improves beta‐cell function in patients with acute coronary syndromes and newly diagnosed glucose abnormalities–the BEGAMI study
Hage, C., Brismar, K., Efendić, S., Lundman, P., Rydén, L., & Mellbin, L. (2013) · Journal of Internal Medicine · doi:10.1111/joim.12032 · Cited by 22
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“GLP-1 also inhibits apoptosis of isolated human b-cells and enhances their glucose responsiveness (76).”
Background
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Bosi, E., Lucotti, P., Setola, E., Monti, L. D., & Piatti, P. M. (2008) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2008.10.003 · Cited by 22
Protecting Pancreatic ß‐cells
Pileggi, A., Fenjves, E., Klein, D., Ricordi, C., & Pastori, R. (2004) · IUBMB Life · doi:10.1080/15216540400006469 · Cited by 22
“Glucagon-Like Peptide-1 (GLP-1) Prevention of islet cell apoptosis (reduced nuclear condensation and fragmentation, reduced caspase 3 activation) and improved in vitro function in human islets (55) Insulin-Like Growth”
Background
Incretin-Based Therapy and the Quest for Sustained Improvements in β-Cell Health
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“Both GLP-1 and GIP also exhibit robust proliferative and antiapoptotic actions on rodent b-cells in experimental models of type 2 diabetes (3), and GLP-1 exerts salutary effects on the molecular mechanisms underlying b-cell function and enhances b-cell survival in studies with human islets cultured ex vivo (4,5).”
Background
Anti-inflammatory effects of GLP-1 in patients with COVID-19
Sazgarnejad, S., Yazdanpanah, N., & Rezaei, N. (2022) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2021.1964955 · Cited by 21
“of anti-apoptotic factors such as Bcl-2 [29].”
Influential
Second line therapy: type 2 diabetic subjects failing on metformin GLP‐1/DPP‐IV inhibitors versus sulphonylurea/insulin: For GLP‐1/DPP‐IV inhibitors
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Incretin-Based Therapies
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“GLP-1 has also been shown to have beneficial effects on β-cell function in animal models and in human islets studied in vitro.(43,44) Because of these differences, therapies that are based on the actions of GLP-1 are more attractive for the treatment of type 2 diabetes.”
Background
Liraglutide for treating type 1 diabetes
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“Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum.”
BackgroundInfluential
Gut feelings about diabetes
Laferrère, B. (2012) · Endocrinología y Nutrición · doi:10.1016/j.endonu.2012.01.010 · Cited by 18
Ketosis-Prone Type 2 Diabetes: A Case Series
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Gastrointestinal Tract and Endocrine System
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“In vitro and animal studies have shown that GLP-1A exerts trophic effects on the pancreatic β cells, stimulating proliferation and differentiation, ultimately leading to an increased risk of PC and reducing β-cell apoptosis.(22,23) In addition, based on the results from preliminary studies, a β cell–preserving effect…”
Background
Arrestin‐independent internalization of the GLP ‐1 receptor is facilitated by a GRK , clathrin, and caveolae‐dependent mechanism
Moo, E. V., Møller, T. C., Sørensen, F. A., Inoue, A., & Bräuner‐Osborne, H. (2025) · FEBS Journal · doi:10.1111/febs.17338 · Cited by 19
“GLP-1R-mediated Gs/cAMP/PKA signaling leads to insulin secretion, preservation of functional beta-cell mass, and has protective effect on beta cell glucotoxicity and lipotoxicity [2,26,86].”
Add-on therapies to metformin for type 2 diabetes
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“Traditionally, treatments for type 2 diabetes have had little impact on important factors in the pathogenesis of the disease, including the progressive decline of b-cell function and reductions in the contributions of the incretin hormones to glucose regulation [2-4].”
Background
Evaluation of 18F-labeled exendin(9-39) derivatives targeting glucagon-like peptide-1 receptor for pancreatic β-cell imaging
Kimura, H., Ogawa, Y., Fujimoto, H., Mukai, E., Kawashima, H., Arimitsu, K., Toyoda, K., Fujita, N., Yagi, Y., Hamamatsu, K., et al. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.12.007 · Cited by 18
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“11 of GLP-1(7-36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides.”
BackgroundInfluential
Fc fusion to Glucagon-like peptide-1 inhibits degradation by human DPP-IV, increasing its half-life in serum and inducing a potent activity for human GLP-1 receptor activation
Kim, D.-M., Chu, S.-H., Kim, S., Park, Y.-W., & Kim, S.-S. (2009) · BMB Reports · doi:10.5483/bmbrep.2009.42.4.212 · Cited by 18
“ever, its very short half-life, which is primarily caused by degradation by DPP-IV, inhibits its clinical application (15-17).”
Background
The Sequential Combination of a JNK Inhibitor and Simvastatin Protects Porcine Islets from Peritransplant Apoptosis and Inflammation
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Authors: Farilla, L., Bulotta, A., Hirshberg, B., Li Calzi, S., Khoury, N., Noushmehr, H., Bertolotto, C., Di Mario, U., Harlan, D. M., & Perfetti, R.
Affiliations: Cedars-Sinai Medical Center (US)
National Institutes of Health (US)
Corresponding author: Perfetti, Riccardo
ORCID: Hirshberg, Boaz
Noushmehr, Houtan
Harlan, David M.
Perfetti, Riccardo
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2003-12
Volume: 144
Issue: 12
Pages: 5149-5158
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2003-0323
OpenAlex: W2146333376
Cited by: 664
References: 34
Citations by year: 2026: 6 · 2025: 14 · 2024: 12 · 2023: 11 · 2022: 14 · 2021: 24 · 2020: 15 · 2019: 26 · 2018: 26 · 2017: 23 · 2016: 32 · 2015: 28 · 2014: 36 · 2013: 50 · 2012: 40
FWCI: 23.65
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords: glucagon-like peptide-1, beta-cell apoptosis, human pancreatic islets, glucose-dependent insulin secretion, caspase-3, Bcl-2, islet viability, islet morphology, insulin content, islet transplantation, diabetes mellitus
MeSH terms: Insulin Secretion, Cell Survival, Cells, Cultured, Fluorescent Antibody Technique, Fluorescent Dyes, Glucagon, Glucose, Humans, Indoles, Insulin, Islets of Langerhans, Peptide Fragments, Protein Precursors, RNA, Messenger, Gene Expression, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Reverse Transcriptase Polymerase Chain Reaction, Caspases, Glucagon-Like Peptide 1, Caspase 3, In Vitro Techniques

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Glucagon-Like Peptide 1 Inhibits Cell Apoptosis and Improves Glucose Responsiveness of Freshly Isolated Human Islets

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