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
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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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Background
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Therapeutic Strategies Targeting Pancreatic Islet β-Cell Proliferation, Regeneration, and Replacement
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Self-citation
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Background
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Background
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Background
Improved Human Islet Preparations Using Glucocorticoid and Exendin-4
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Background
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Background
Comparing the Effectiveness of Total Gastrectomy and Gastric Bypass on Glucose Metabolism in Diabetic Rats
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“Importantly, glucagon-like peptide-1 (GLP-1) exerts antiapoptotic effects [14,15], counteracting cytokine action and gene expression [16,17].”
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Background
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Background
Baseline red blood cell distribution width predicts long-term glycemic remission in patients with type 2 diabetes
Xu, L., Wang, L., Huang, X., Liu, L., Ke, W., He, X., Huang, Z., Liu, J., Wan, X., Cao, X., et al. (2017) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2017.06.019 · Cited by 8
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Self-citation
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Background
Glucagon-like peptide analogues for type 2 diabetes mellitus
Snaith, A., McIntyre, L., Rothnie, H. M., Thomas, S., Royle, P., & Waugh, N. R. (2007) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006423 · Cited by 9
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Incretin-Based Therapy for Type 2 Diabetes Mellitus
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“01).(37) Hence, the available evidence suggests that GLP-1R signaling pathways are highly conserved in rodent versus human islets.”
Background
Pharmacological characterization and antidiabetic activity of a long‐acting glucagon‐like peptide‐1 analogue conjugated to an antithrombin III ‐binding pentasaccharide
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“The ability of the GLP-1 conjugate at 100 nmol/kg to arrest this decline and for all incretin mimetic-treated groups to display increased islet area presumably reflects the established β-cell sparing and islet protective effects of GLP-1 [32]; however, there were no obvious changes in overall islet cell proliferation…”
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Structural Requirements for some 3-amino-N-substituted-4-(substituted phenyl) Butanamides as Dipeptidyl Peptidase-IV Inhibitors Using 3D-QSAR and Molecular Docking Approaches
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“DPP-IV, a serine protease, specifically cleaves N-terminal dipeptides from substrates containing proline and to some extent alanine, at the penultimate position as in GLP-1 is responsible for very short half-life of the latter (only 1-2 min) and GIP (7 min)[6,7].”
Background
Oral glucagon-like peptide 1 analogue ameliorates glucose intolerance in db/db mice
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Incretins and islet function
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Neue orale Antidiabetika
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“Beide Inkretinhormone stimulieren im Tiermodell und an isolierten humanen Inselzell-Linien die β-Zellproliferation (GLP-1: Tiermodell und isolierte humane Inselzellen, GIP: isolierte Inselzell-Linien; [7]).”
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Concurrent Adult-Onset Diffuse β-Cell Nesidioblastosis and Pancreatic Neuroendocrine Tumor: A Case Report and Review of the Literature
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Cw, C., Jm, E., Chia, C. W., Egan, J. M., correspondence, A., & Egan, J. M. (2014) · Cited by 6
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Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1
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Quintana, J. M., Stinchcomb, A. L., Kostyo, J. H., Robichaud, B., Plunk, M. A., & Kane, R. R. (2018) · OBM Transplantation · doi:10.21926/obm.transplant.1804036 · Cited by 6
GAD‐65 antibodies in a case of HNF1A‐Maturity‐Onset Diabetes of the Young: Double diabetes?
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Gene Expression Profiling of Cultured Human Islet Preparations
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Self-citation
Dual-Target Insight into Drug Discovery from Natural Products as Modulators of GLP-1 and the TXNIP–Thioredoxin Antioxidant System in Metabolic Syndrome
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“(5) Preservation of β -Cell Function : Research indicates that GLP-1 inhibits apoptosis and stimulates β -cell neogenesis and proliferation, which helps maintain functional β -cell mass over time [22,23].”
Is there U-turn from Insulin Back to Pills in Diabetes?
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A novel refined classification system for type 2 diabetes in adults: A Chinese retrospective cohort study
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¿Es la diabetes mellitus tipo 2 una enfermedad de tratamiento quirurgico?
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A case of insulinoma following total gastrectomy—Effects of an alpha-glucosidase inhibitor on suppressing GIP and GLP-1 elevations
Sato, T. K., Narita, T., Hosoba, M., Kakei, M., Nanjo, H., Uchinami, H., Satoh, K., Yamamoto, Y., & Yamada, Y. (2010) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2010.01.006 · Cited by 5
Exendin-4 effects on islet volume and number in mouse pancreas
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“It has also been shown that human islets treated with GLP-1 have a down-regulation of caspase-3 at the levels of mRNA of the active protein and up-regulation of the anti-apoptotic protein Bcl-2 (Farilla et al., 2003).”
Preservation of pancreatic islets in cold UW solution before transplantation
Ishii, S., Saito, T., Ise, K., Yamashita, M., Sato, Y., Saito, T., Tsukada, M., Oshibe, I., Kenjo, A., Kimura, T., et al. (2012) · Islets · doi:10.4161/isl.18607 · Cited by 5
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The Incretin Modulators – Incretin Mimetics (GLP-1 Receptor Agonists) and Incretin Enhancers (DPP-4 Inhibitors)
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“However, although some experiments with human islets or islet cell precursors have reported similar findings [65,214], only preliminary hints have been gained from clinical studies examining the long-term effect of incretin mimetics on parameters of “β-cell health.”
BackgroundResultInfluential
Incretins and SGLT-2 inhibitors in diabetic patients with neuroendocrine tumors: current updates and future directions
Ruggeri, R. M., Grossrubatscher, E. M., Ciocca, E., Hasballa, I., Jaafar, S., Oldani, M., Rubino, M., Russo, F., Isidori, A. M., Colao, A. A. L., et al. (2025) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-025-09958-5 · Cited by 5
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GLP-1RA and SGLT2i: Cardiovascular Impact on Diabetic Patients
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FARMACOLOGIA DO DIABETES MELLITUS TIPO 2: ANTIDIABÉTICOS ORAIS, INSULINA E INOVAÇÕES TERAPÊUTICAS
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Nuevas terapias en diabetes: más allá de la insulina inyectable y de los antidiabéticos orales
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Improved transplantation outcome through delivery of DNA encoding secretion signal peptide-linked glucagon-like peptide-1 into mouse islets
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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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