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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Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen
Shapiro, A. M. J., Lakey, J. R. T., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M., & Rajotte, R. V. (2000) · New England Journal of Medicine · doi:10.1056/nejm200007273430401 · Cited by 5,237
Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats.
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“It has been demonstrated that the role of GLP-1 extends beyond its glucose-lowering action in response to food ingestion and included the de novo synthesis of proinsulin (2).”
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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Self-citation
Glucagon-Like Peptide 1 Induces Pancreatic β-Cell Proliferation Via Transactivation of the Epidermal Growth Factor Receptor
Buteau, J., Foisy, S., Joly, E., & Prentki, M. (2003) · Diabetes · doi:10.2337/diabetes.52.1.124 · Cited by 411
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Glucagon-Like Peptide-1 and Exendin-4 Stimulate β-Cell Neogenesis in Streptozotocin-Treated Newborn Rats Resulting in Persistently Improved Glucose Homeostasis at Adult Age
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“GLP-1 also has proliferative and anti-apoptotic effects on the b-cell [12,13].”
Background
Do we really know why diabetes remits after gastric bypass surgery?
Laferrère, B. (2011) · Endocrine · doi:10.1007/s12020-011-9514-x · Cited by 53
“Although GLP-1 has been shown to preserve human islet in vitro [35] and prevent beta cell apoptosis in rodents [36] there is no human data to suggest that GLP-1 increases beta cell mass after bypass in humans.”
Biliopancreatic diversion in rats is associated with intestinal hypertrophy and with increased GLP-1, GLP-2 and PYY levels
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“Native GLP-1 has been shown to exert direct antiapoptotic effects on human [74] and rodent [56] b cells.”
Background
Terpenoids as potential phytoconstituent in the treatment of diabetes: From preclinical to clinical advancement
Roy, S., Ghosh, A., Majie, A., Karmakar, V., Das, S., Dinda, S. C., Bose, A., & Gorain, B. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155638 · Cited by 58
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“One possible explanation is the protection of β-cell mass by the inhibition of apoptosis [47-49].”
Background
Taspoglutide, an Analog of Human Glucagon-Like Peptide-1 with Enhanced Stability and in Vivo Potency
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“While there may be benefit to the peri-transplant use of glucagon-like peptide-1 (GLP-1) agonists for an anti-apoptotic effect on human islet β-cells [60], clinical studies adding the GLP-1 agonist exenatide have also added etanercept and, so, attribution of benefit cannot be ascribed to exenatide alone [59, 61].”
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“GLP-1R can activate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway leading to protection against apoptosis and inhibition of pro-inflammatory cytokines (Farilla et al., 2003; Grieco et al., 2019; Tramutola et al., 2017; Yang et al., 2018).”
Background
Pathophysiology of Type 2 Diabetes and the Role of Incretin Hormones and Beta-Cell Dysfunction
Fujioka, K. (2007) · JAAPA · doi:10.1097/01720610-200712000-00001 · Cited by 51
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“Moreover, the incretins have protective effects on pancreatic β-cells by enhancing their proliferation and increasing their resistance to apoptosis.(4,5) Other beneficial aspects of GLP-1 are the slowing of gastric emptying and the induction of satiety,(6) supporting dietary goals in diabetes treatment.”
Background
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Evaluation of the INS-1 832/13 Cell Line as a Beta-Cell Based Screening System to Assess Pollutant Effects on Beta-Cell Function
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Effects of exendin‐4 on islets from type 2 diabetes patients
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“A growing body of evidence suggests that glucagon-like peptide 1 (GLP-1) and its analogues ameliorate experimental diabetes and preserve β-cell mass, protecting β-cells from apoptosis [93–95].”
Background
GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice
Kawamori, D., Shirakawa, J., Liew, C. W., Hu, J., Morioka, T., Duttaroy, A., Burkey, B. F., & Kulkarni, R. (2017) · Diabetologia · doi:10.1007/s00125-017-4303-6 · Cited by 46
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“Although GLP1 therapies have shown increased β-cell proliferation (Edvell and Lindström, 1999; Liu and Habener, 2008; Gaddy et al., 2010), we did not see a significant increase in β-cell proliferation upon Glp1 gene therapy.”
Background
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Epstein, S., Defeudis, G., Manfrini, S., Napoli, N., & Pozzilli, P. (2016) · Osteoporosis International · doi:10.1007/s00198-015-3454-x · Cited by 46
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“A recent in vitro study on cultured human islets showed that GLP-1 inhibited apoptosis during the 5 days of observation [26].”
Background
The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation
Park, Y. J., Ao, Z., Kieffer, T. J., Chen, H., Safikhan, N., Thompson, D. M., Meloche, M. R., Warnock, G. L., & Marzban, L. (2012) · Diabetologia · doi:10.1007/s00125-012-2802-z · Cited by 44
“In support, a previous study has reported that treatment with GLP-1 increases beta cell insulin content in human isolated islets [34].”
Result
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“Remarkably, it also preserves pancreatic β cell function by inducing their proliferation and inhibiting their apoptosis [2].”
Background
GLP-1 agonists in type 1 diabetes
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“It also promotes the survival and proliferation of pancreatic beta-cells [18,19].”
Background
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Gallwitz, B. (2010) · Pediatric Nephrology · doi:10.1007/s00467-009-1435-z · Cited by 42
“Since GLP-1 has a positive effect on beta cell mass in rodents as well as a beneficial effect on the survival of isolated human islets in cell culture [6, 104, 105], it is imaginable that incretin-based therapies may also be advantageous in type 1 diabetes, possibly in combination with immune therapy.”
Background
Minireview: Signal Bias, Allosterism, and Polymorphic Variation at the GLP-1R: Implications for Drug Discovery
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“The cytoprotective actions of GLP-1 also promote survival of human islets (21,22).”
Background
Medicinal Chemistry of Incretin Mimetics and DPP‐4 Inhibitors
Zettl, H., Schubert‐Zsilavecz, M., & Steinhilber, D. (2009) · ChemMedChem · doi:10.1002/cmdc.200900448 · Cited by 42
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“Publishe Apart from the effects on insulin secretion, incretins also increase β-cell proliferation [8,9], exert an antiapoptotic effect by upregulating bcl-2 and bcl-xL proteins [10], induce proinsulin gene expression and insulin biosynthesis [11], and may have beneficial effects in the early stages of diabetic nephro…”
Background
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“Insulinotropic agents such as repaglinide or GLP-1 have been shown to be cytoprotective in-vitro and in animal models of diabetes [36,37].”
Background
Correlation Between Baseline Characteristics and Clinical Outcomes in a Large Population of Diabetes Patients Treated with Liraglutide in a Real-World Setting in Italy
Lapolla, A., Frison, V., Bettio, M., Pos, M. D., Rocchini, P., Panebianco, G., Tadiotto, F., Tos, V. D., D׳Ambrosio, M., Marangoni, A., et al. (2015) · Clinical Therapeutics · doi:10.1016/j.clinthera.2014.11.015 · Cited by 39
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“Fluorescent micrographs of islets revealed that by culture day 3, islets treated with exendin-4 exhibited significantly less apoptosis, lesser amounts of activated caspase-3, and greater amounts of Bcl-2 than control islets (8).”
Background
Potential New Approaches to Modifying Intestinal GLP-1 Secretion in Patients with Type 2 Diabetes Mellitus
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Self-citation
Treatment of diabetic rats with encapsulated islets
Sweet, I. R., Yanay, O., Waldron, L., Gilbert, M. L., Fuller, J. M., Tupling, T., Lernmark, Å., & Osborne, W. R. A. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00322.x · Cited by 39
“Prolonged bioactivity of islets coencapsulated with polymerized synthetic GLP-1 has been described [41].”
BackgroundInfluential
Glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase IV inhibitors: new therapeutic agents for the treatment of type 2 diabetes
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“Ageing is associated with physiologic disturbance in glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), which have a role in maintaining β-cells growth and proliferation, contributing to β-cells dysfunction [43,44].”
Background
Modulation of GLP-1 signaling as a novel therapeutic approach in the treatment of Alzheimer’s disease pathology
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“However, there is strong evidence to suggest that GLP-1 receptor activation can protect beta-cells from apoptosis [94– 97] and equally convincing evidence of a beta-cell mitogenic effect of GLP-1 [93, 94, 98, 99].”
Background
Type 2 Diabetes: An Expanded View of Pathophysiology and Therapy
Unger, J., & Parkin, C. G. (2010) · Postgraduate Medicine · doi:10.3810/pgm.2010.05.2152 · Cited by 36
Miglitol administered before breakfast increased plasma active glucagon-like peptide-1 (GLP-1) levels after lunch in patients with type 2 diabetes treated with sitagliptin
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“insulin resistance [22, 23] and GLP-1 reportedly inhibits apoptosis in humans, the increase in the GLP-1 concentration may be important for improving beta cell function [24].”
Background
GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products
Guglielmi, V., & Sbraccia, P. (2016) · Eating and Weight Disorders - Studies on Anorexia Bulimia and Obesity · doi:10.1007/s40519-016-0352-y · Cited by 37
The effect of glucagon-like peptide 1 and glucagon-like peptide 1 receptor agonists on energy expenditure: A systematic review and meta-analysis
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“In isolated human islets, glucose-dependent insulin secretion and islet cell morphology is significantly improved, when the islets are incubated with GLP-1 [32].”
Background
Effects of dextromethorphan as add‐on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo‐controlled, double‐blinded, multiple crossover, single‐dose clinical trial
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“Our findings now warrant further and long-term clinical trials on the combined action of DXM and incretin-based diabetes therapies so as to draw conclusions on the clinical relevance of this combination, in particular concerning the preservation of β-cell function and mass that has been described for DXM in preclinica…”
Background
Impact of bariatric surgery on type 2 diabetes
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Characterization of Islet Preparations
Colton, C. K., Papas, K. K., Pisania, A., Rappel, M. J., Powers, D. E., O’Neil, J. J., Omer, A., Weir, G. C., & Bonner‐Weir, S. (2007) · Elsevier eBooks · doi:10.1016/b978-012369415-7/50007-7 · Cited by 35
Semaglutide Ameliorates Diabetic Neuropathic Pain by Inhibiting Neuroinflammation in the Spinal Cord
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“GLP-1 is also well known for its neuroprotective and cardioprotective properties, which include anti-apoptotic [28] and anti-inﬂammatory effects [29], and its inﬂuence on memory, learning, palatability, and reward behavior [30,31].”
The direct effects of GLP-1 and GIP, alone or in combination, on human pancreatic islets
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Liraglutide prevents high glucose level induced insulinoma cells apoptosis by targeting autophagy
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“Subsequent in vitro studies by this group demonstrated similar benefits in human pancreatic islets; the addition of GLP-1 to freshly isolated islets preserved their morphology and function and reduced cellular apoptosis.(60)”
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Background
The role of the CCL25-CCR9 axis in beta-cell function: potential for therapeutic intervention in type 2 diabetes
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Role of Gut-Related Peptides and Other Hormones in the Amelioration of Type 2 Diabetes after Roux-en-Y Gastric Bypass Surgery
Hage, M. P., Safadi, B. Y., Salti, I., & Nasrallah, M. (2012) · ISRN Endocrinology · doi:10.5402/2012/504756 · Cited by 35
“It enhances glucose-dependent insulin release and improves beta cell function [42, 43].”
Background
Liraglutide prevents β-cell apoptosis via inactivation of NOX2 and its related signaling pathway
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Mechanism of glucagon-like peptide 1 improvements in type 2 diabetes mellitus and obesity.
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“In vitro, GLP-1RA can suppress cell apoptosis and enhance glucose response in freshly isolated human islets (113).”
Background
Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets
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Background
Liraglutide Therapy for Type 2 Diabetes: Overcoming Unmet Needs
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Background
Chronic Exposure to GLP-1 Increases GLP-1 Synthesis and Release in a Pancreatic Alpha Cell Line (α-TC1): Evidence of a Direct Effect of GLP-1 on Pancreatic Alpha Cells
Piro, S., Mascali, L. G., Urbano, F., Filippello, A., Malaguarnera, R., Calanna, S., Rabuazzo, A. M., & Purrello, F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090093 · Cited by 34
“GLP-1 was replaced every 12 hours, as previously described [26].”
Method
Effects of novel antidiabetes agents on apoptotic processes in diabetes and malignancy: Implications for lowering tissue damage
Yaribeygi, H., Lhaf, F., Sathyapalan, T., & Sahebkar, A. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.06.013 · Cited by 34
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Background
Pharmacology, efficacy and safety of liraglutide in the management of type 2 diabetes
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“Agents which mimic the incretin system, such as GLP-1 agonists, have a low incidence of hypoglycemia, often cause weight loss, and may preserve β-cells or even stimulate their proliferation.(11,12) In addition to the approval of exenatide, liraglutide was approved by the FDA in January 2010.”
Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect?
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An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes
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“Furthermore, GLP1 has been shown to improve glucose sensitivity to glucoseresistant ββ cells [29–31].”
Background
Changes of Dipeptidyl Peptidase IV (DPP-IV) in Obese Children with Weight Loss: Relationships to Peptide YY, Pancreatic Peptide, and Insulin Sensitivity
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Use of additives, scaffolds and extracellular matrix components for improvement of human pancreatic islet outcomes in vitro: A systematic review
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Gastrointestinal surgery and gut hormones
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Bariatric Surgery in Type 1 Diabetes Mellitus: A Systematic Review
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Synergy Between Gαz Deficiency and GLP-1 Analog Treatment in Preserving Functional β-Cell Mass in Experimental Diabetes
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Inhibition of the MAP3 kinase Tpl2 protects rodent and human β-cells from apoptosis and dysfunction induced by cytokines and enhances anti-inflammatory actions of exendin-4
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“analogs protect β-cell survival and function from proinflammatory cytokine attack.(12,14,15) However, some studies have”
Background
Medicinal chemistry of non-peptidomimetic dipeptidyl peptidase IV (DPP IV) inhibitors for treatment of Type-2 diabetes mellitus: Insights on recent development
Ambhore, J. P., Laddha, P. R., Nandedkar, A., Ajmire, P. V., Chumbhale, D. S., Navghare, A. B., Kuchake, V., Chaudhari, P. J., & Adhao, V. S. (2023) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2023.135249 · Cited by 27

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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