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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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“β-Cell trophic effects of the incretin mimetics and DPP-4 inhibitors have, thus far, only been seen in animal studies and in vitro (β-cell lines and isolated human islets) [54-57], but beneficial effects on islet function have been seen in both animal and human studies.”
BackgroundVergès, B., Bonnard, C., & Renard, E. (2011) · Diabetes & Metabolism · doi:10.1016/j.diabet.2011.07.001 · Cited by 58
“[12] Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, et al.”
BackgroundAntwi, K., Nicolas, G., Fani, M., Heye, T. J., Pattou, F. N., Grossman, A. B., Chanson, P., Reubi, J. C., Perren, A. A., Gloor, B., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02754 · Cited by 58
Synthesis of dipeptidyl peptidase-4 inhibitors: a brief overview
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“It has also been suggested, on the basis of in vitro studies with human islets, that GLP-1 receptor agonists are capable of preserving islet morphology [18], while in vitro and in vivo studies examining rodent islets suggest that GLP-1 receptor agonists may preserve or even increase beta cell mass [19–22].”
Gaal, L. F. V., Gutkin, S. W., & Nauck, M. A. (2008) · European Journal of Endocrinology · doi:10.1530/eje-07-0804 · Cited by 58
“ActivationofGIPreceptors,whicharemainlyexpressedon islet b-cells, adipocytes, and cells in the central nervous system (CNS), among other actions, helps to prevent apoptosis and foster survival of human b-cells ( 47 ).”
BackgroundGLP-1R agonist therapy for diabetes: benefits and potential risks
Samson, S. L., & Garber, A. (2013) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e32835edb32 · Cited by 55
“In preclinical studies, GLP-1 has been shown to protect b-cells [5].”
Backgroundde Souza, C. O., Sun, X., & Oh, D. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.715877 · Cited by 63
Immortalized neurons for the study of hypothalamic function
Dalvi, P. S., Nazarians-Armavil, A., Tung, S., & Belsham, D. D. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00649.2010 · Cited by 56
“On the basis of the findings that GLP-1 inhibits pancreatic -cell apoptosis and stimulates their proliferation (77) and that GLP-2 induces intestinal epithelial proliferation (64), it is likely that both may play an important role in exerting CNTF-induced neurogenesis.”
BackgroundTreatment of Type 1 Diabetic Patients with Glucagon-Like Peptide-1 (GLP-1) and GLP-1R Agonists
Kielgast, U. L., Holst, J. J., & Madsbad, S. (2009) · Current Diabetes Reviews · doi:10.2174/157339909789804413 · Cited by 56
“In rodent models of type 2 diabetes or insulin resistance, GLP-1 has been shown to promote ß-cell neogenesis, proliferation and differentiation and inhibit apoptosis in vivo, thereby increasing ß-cell mass [25-32].”
Hepatoprotective potential of isoquercitrin against type 2 diabetes-induced hepatic injury in rats
Huang, X., He, Y., Ji, L.-L., Wang, K., Wang, Y., Chen, D., Geng, Y., Ouyang, P., & Lai, W. (2017) · Oncotarget · doi:10.18632/oncotarget.21074 · Cited by 56
Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes
Tanday, N., Flatt, P. R., Irwin, N., & Moffett, R. C. (2020) · Journal of Endocrinology · doi:10.1530/joe-19-0451 · Cited by 56
Inventing Liraglutide, a Glucagon-Like Peptide-1 Analogue, for the Treatment of Diabetes and Obesity
Knudsen, L. B. (2019) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.9b00048 · Cited by 59
Glucagon‐like peptide‐1 receptor is expressed in human and rodent testis
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“…cells was significantly improved by treatment with medium supplemented with amino acids, vitamins and inorganic salts (Tsang et al., 2007), all-trans-retinoic acid (Lee et al., 2008) or, maybe, GLP-1 receptor agonists by reducing apoptosis and maintaining islet integrity (Farilla et al., 2003).”
BackgroundFujii, Y., Osaki, N., Hase, T., & Shimotoyodome, A. (2015) · Journal of Nutritional Science · doi:10.1017/jns.2014.71 · Cited by 55
Bariatric surgery and obesity: influence on the incretins
Laferrère, B. (2016) · International Journal of Obesity Supplements · doi:10.1038/ijosup.2016.8 · Cited by 55
Complications of Diabetes Therapy
Corathers, S. D., Peavie, S., & Salehi, M. (2013) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2013.06.005 · Cited by 58
GLP-1 Agonists and Dipeptidyl-Peptidase IV Inhibitors
Gallwitz, B. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-17214-4_3 · Cited by 56
“Since GLP-1 has a positive effect on beta-cell mass in rodents as well as a beneficial effect on survival of isolated human islets in cell culture (Baggio and Drucker 2007; Drucker and Nauck 2006; Farilla et al. 2003), incretin-based therapies might also 68 B.”
BackgroundGhazi, T., Rink, L., Sherr, J. L., & Herold, K. C. (2013) · Diabetes Care · doi:10.2337/dc13-1169 · Cited by 55
“Moreover, animal studies have suggested that GLP-1 therapy may promote the proliferation of b-cells, enhance b-cell recovery, and suppress b-cell apoptosis (9,10), suggesting that there may be long-term primary benefit to its use.”
Cuthbertson, J., Patterson, S., O'Harte, F. P. M., & Bell, P. M. (2010) · Metabolism · doi:10.1016/j.metabol.2010.01.001 · Cited by 51
“It may enhance insulin sensitivity [3] and, by stimulating β-cell regeneration and inhibition of apoptosis [4], holds out the prospect of altering the natural history of type 2 diabetes mellitus.”
BackgroundManagement of postgastric bypass noninsulinoma pancreatogenous hypoglycemia
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“It also has been shown to prevent apoptosis in freshly isolated human islets [21], but there are no in vivo studies in humans.”
BackgroundAn update on preventive and regenerative therapies in diabetes mellitus
Reimann, M., Bonifacio, E. E., Solimena, M., Schwarz, P. E. H., Ludwig, B., Hanefeld, M., & Bornstein, S. R. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.11.009 · Cited by 53
“…mimetics and DPP-4 inhibitors have been especially suggested as a therapeutic option, due to proliferative, neogenic, and antiapoptotic actions (Farilla et al., 2003; Pospisilik et al., 2003; Liu & Habener, 2008), but their long-term effects on beta-cell mass in patients with diabetes remains…”
Background
Metadata
- 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 › 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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