Glucagon-Like Peptide 1 Inhibits Cell Apoptosis and Improves Glucose Responsiveness of Freshly Isolated Human Islets
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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The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits β-cell apoptosis in vitro
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Unraveling the Science of Incretin Biology
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“Invitro studies indicate thatGLP-1protectsβcells from the threat of cell death induced by elevated levels of glucose and lipids, and helps to maintain islet cell morphology [44,52].”
BackgroundFoxa1 and Foxa2 Control the Differentiation of Goblet and Enteroendocrine L- and D-Cells in Mice
Ye, D. Z., & Kaestner, K. H. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.08.059 · Cited by 168 · see citing works
“neogenesis, and prevents β-cell apoptosis [55–58].”
McLaughlin, T., Peck, M., Holst, J., & Deacon, C. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1628 · Cited by 183 · see citing works
Gautier, J. F., Fetita, S., Sobngwi, E., & Salaun-Martin, C. (2005) · Diabetes & Metabolism · doi:10.1016/s1262-3636(07)70190-8 · Cited by 163 · see citing works
“Recent data indicate that the antiapoptotic effects were also observed in freshly isolated human islets cultures in vitro [34].”
Beta cell mass in diabetes: a realistic therapeutic target?
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β-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A Perspective on Islet Plasticity
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Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes
Richter, B. (2008) · Vascular Health and Risk Management · doi:10.2147/vhrm.s1707 · Cited by 152 · see citing works
“Direct effects of GLP-1 on β -cell growth and survival could be demonstrated in animal models, with GLP-1 stimulated proliferation and differentiation of new β -cells together with an inhibition of β -cell apoptosis (Xu et al 1999; Perfetti et al 2000; Stoffers et al 2000; Farilla et al 2003).”
Dipeptidyl Peptidase‐4 Inhibitors for the Treatment of Type 2 Diabetes Mellitus
Neumiller, J. J., Wood, L. D., & Campbell, R. K. (2010) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.30.5.463 · Cited by 150 · see citing works
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Therapeutic Approaches to Preserve Islet Mass in Type 2 Diabetes
Baggio, L. L., & Drucker, D. J. (2006) · Annual Review of Medicine · doi:10.1146/annurev.med.57.110104.115624 · Cited by 149 · see citing works
Friedrichsen, B. N., Neubauer, N., Lee, Y. C., Gram, V. K., Blume, N., Petersen, J. S., Nielsen, J. H., & Møldrup, A. (2006) · Journal of Endocrinology · doi:10.1677/joe.1.06160 · Cited by 147 · see citing works
“The role of incretins as regulators of -cell replication (Farilla et al. 2003) and anti-apoptosis that have been recently described (Hui et al. 2003, Urusova et al. 2004, Bregenholt et al. 2005) may be of particular importance since functional -cells are progressively lost during development of…”
BackgroundNeumiller, J. J. (2009) · Journal of the American Pharmacists Association · doi:10.1331/japha.2009.09078 · Cited by 144 · see citing works
Glucagon-like Peptide–1 Analogues for Type 2 Diabetes Mellitus: Current and Emerging Agents
Gallwitz, B. (2011) · Drugs · doi:10.2165/11592810-000000000-00000 · Cited by 142 · see citing works
“of isolated human islets in cell culture([14,24,96]) gives rise to the hypothesis that incretin-based therapies might also prove advantageous in type 1 diabetes alone or in combination with immune therapy.”
Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue
Russell-Jones, D. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.11.018 · Cited by 137 · see citing works
Kim, S., Nian, C., Widenmaier, S. B., & McIntosh, C. H. S. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00325-07 · Cited by 137 · see citing works
“GLP-1 (4, 12, 15, 16, 25, 55), have also been shown to involve”
BackgroundInfluentialSanz, C., Vázquez, P., Blázquez, C. P., Barrio, P. A., Álvarez, M., & Blázquez, E. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00460.2009 · Cited by 135 · see citing works
Kielgast, U., Holst, J. J., & Madsbad, S. (2011) · Diabetes · doi:10.2337/db10-1790 · Cited by 137 · see citing works
“In freshly isolated human islets, GLP-1 has been reported to inhibit b-cell apoptosis (23).”
BackgroundSurvival of encapsulated islets: More than a membrane story
Barkai, U., Rotem, A., & de Vos, P. (2016) · World Journal of Transplantation · doi:10.5500/wjt.v6.i1.69 · Cited by 129 · see citing works
Effect of Exenatide on ?? Cell Function After Islet Transplantation in Type 1 Diabetes
Ghofaili, K. A., Fung, M., Ao, Z., Meloche, M. R., Shapiro, R. J., Warnock, G. L., Elahi, D., Meneilly, G. S., & Thompson, D. M. (2007) · Transplantation · doi:10.1097/01.tp.0000251379.46596.2d · Cited by 130 · see citing works
“Studies, including those using human islets (19), that show exenatide causing cell proliferation and/or decreased apoptosis have generally used concentrations of 10 nM with a duration of exenatide exposure of days to weeks (8).”
BackgroundMinireview: Update on Incretin Biology: Focus on Glucagon-Like Peptide-1
Brubaker, P. L. (2010) · Endocrinology · doi:10.1210/en.2010-0115 · Cited by 122 · see citing works
“Notwithstanding these findings, markers of apoptosis are increased in islets from humans with T2D (31), and apoptosis has been found to be reduced by GLP-1 treatment of human islets in vitro (37).”
Marzook, A., Tomas, A., & Jones, B. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.678055 · Cited by 121 · see citing works
“These findings further support the claim that sustained GLP-1R agonism may result in disease modifying activity in people with T2D through enhancement or preservation of functional beta cell mass (35).”
BackgroundSingh, V., Brendel, M., Zacharias, S., Mergler, S., Jahr, H., Wiedenmann, B., Bretzel, R., Plöckinger, U., & Strowski, M. (2007) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2006-1578 · Cited by 142 · see citing works
Belsham, D. D., Fick, L. J., Dalvi, P. S., Centeno, M.-L., Chalmers, J. A., Lee, P. K. P., Wang, Y., Drucker, D. J., & Koletar, M. M. (2009) · The FASEB Journal · doi:10.1096/fj.09-133454 · Cited by 120 · see citing works
“Other actions of GLP-1 include islet -cell proliferation, differentiation, and inhibition of apoptosis (32), whereas GLP-2 inhibits enterocyte and crypt-cell apoptosis (17).”
BackgroundIncretin effect: GLP-1, GIP, DPP4
Kazakos, K. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(11)70011-0 · Cited by 120 · see citing works
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The effects of glucagon‐like peptide‐1 on the beta cell
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Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors
Pratley, R. E., & Gilbert, M. P. (2008) · The Review of Diabetic Studies · doi:10.1900/rds.2008.5.73 · Cited by 111 · see citing works
“In addition, activation of the incretin receptors results in other longer term effects, including stimulation of insulin synthesis [17], enhancement of β-cell proliferation, and promotion of resistance to apoptosis [3, 10, 18].”
BackgroundGLP-1, the Gut-Brain, and Brain-Periphery Axes
Cabou, C., & Burcelin, R. (2011) · The Review of Diabetic Studies · doi:10.1900/rds.2011.8.418 · Cited by 110 · see citing works
“Furthermore, GLP-1 increases β-cell mass by stimulating proliferation, inducing islet neogenesis, and inhibiting apoptosis [24-25].”
BackgroundLinagliptin Improves Insulin Sensitivity and Hepatic Steatosis in Diet-Induced Obesity
Kern, M., Klöting, N., Niessen, H. G., Thomas, L. H., Stiller, D., Mark, M., Klein, T., & Blüher, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038744 · Cited by 110 · see citing works
Short Chain Fatty Acids, pancreatic dysfunction and type 2 diabetes
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Emerging Therapies Mimicking the Effects of Amylin and Glucagon-Like Peptide 1
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“The cytoprotective actions of GLP-1R agonists have also been observed in human islets cultured in vitro (113, 114).”
BackgroundTargeting β-Cell Function Early in the Course of Therapy for Type 2 Diabetes Mellitus
Leahy, J. L., Hirsch, I. B., PETERSON, K. A., & Schneider, D. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0668 · Cited by 108 · see citing works
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Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice
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“We found that EGCG promoted human islet viability and preserved its three-dimensional organisation, the typical islet cell aggregates that are crucial for preserving b-cell function((57,58)).”
BackgroundReview article: a comparison of glucagon‐like peptides 1 and 2
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ERK1/2 Control Phosphorylation and Protein Level of cAMP-Responsive Element–Binding Protein
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“Apoptosis was detected by evaluating nuclear condensation (29) and levels of 17-kDa cleaved caspase-3, a key executioner and marker of apoptosis (31,32).”
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Treatment of Type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors
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GLP‐1 (9–36) Amide, Cleavage Product of GLP‐1 (7–36) Amide, Is a Glucoregulatory Peptide
Elahi, D., Egan, J. M., Shannon, R. P., Meneilly, G. S., Khatri, A., Habener, J. F., & Andersen, D. K. (2008) · Obesity · doi:10.1038/oby.2008.229 · Cited by 101 · see citing works
“In rodents, GLP-1 regulates β-cell mass by decreasing apoptosis (5) and increasing the proliferation rate of β-cells (6,7).”
Background
- 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
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2003-12
- Volume
- 144
- Issue
- 12
- Pages
- 5149-5158
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- 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 › Surgery › 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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