Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice
Objective: Type 1 diabetes (T1D) occurs because of islet infiltration by autoreactive immune cells leading to destruction of beta cells and it is becoming evident that beta cell dysfunction partakes in this process. We previously reported that genetic deletion and pharmacological antagonism of the c...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824000371 |
| _version_ | 1797234081284489216 |
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| author | Kanikkai Raja Aseer Caio Henrique Mazucanti Jennifer F. O’Connell Isabel González-Mariscal Anjali Verma Qin Yao Christopher Dunn Qing-Rong Liu Josephine M. Egan Máire E. Doyle |
| author_facet | Kanikkai Raja Aseer Caio Henrique Mazucanti Jennifer F. O’Connell Isabel González-Mariscal Anjali Verma Qin Yao Christopher Dunn Qing-Rong Liu Josephine M. Egan Máire E. Doyle |
| author_sort | Kanikkai Raja Aseer |
| collection | DOAJ |
| description | Objective: Type 1 diabetes (T1D) occurs because of islet infiltration by autoreactive immune cells leading to destruction of beta cells and it is becoming evident that beta cell dysfunction partakes in this process. We previously reported that genetic deletion and pharmacological antagonism of the cannabinoid 1 receptor (CB1) in mice improves insulin synthesis and secretion, upregulates glucose sensing machinery, favors beta cell survival by reducing apoptosis, and enhances beta cell proliferation. Moreover, beta cell specific deletion of CB1 protected mice fed a high fat high sugar diet against islet inflammation and beta cell dysfunction. Therefore, we hypothesized that it would mitigate the dysfunction of beta cells in the precipitating events leading to T1D. Methods: We genetically deleted CB1 specifically from beta cells in non-obese diabetic (NOD; NOD RIP Cre+ Cnr1fl/fl) mice. We evaluated female NOD RIP Cre+ Cnr1fl/fl mice and their NOD RIP Cre− Cnr1fl/fl and NOD RIP Cre+ Cnr1Wt/Wt littermates for onset of hyperglycemia over 26 weeks. We also examined islet morphology, islet infiltration by immune cells and beta cell function and proliferation. Results: Beta cell specific deletion of CB1 in NOD mice significantly reduced the incidence of hyperglycemia by preserving beta cell function and mass. Deletion also prevented beta cell apoptosis and aggressive insulitis in NOD RIP Cre+ Cnr1fl/fl mice compared to wild-type littermates. NOD RIP Cre+ Cnr1fl/fl islets maintained normal morphology with no evidence of beta cell dedifferentiation or appearance of extra islet beta cells, indicating that protection from autoimmunity is inherent to genetic deletion of beta cell CB1. Pancreatic lymph node Treg cells were significantly higher in NOD RIP Cre+ Cnr1fl/fl vs NOD RIP Cre− Cnr1fl/fl. Conclusions: Collectively these data demonstrate how protection of beta cells from metabolic stress during the active phase of T1D can ameliorate destructive insulitis and provides evidence for CB1 as a potential pharmacologic target in T1D. |
| first_indexed | 2024-04-24T16:26:23Z |
| format | Article |
| id | doaj.art-f9b137e5ebbd4b2fba8b127ac6e303d3 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-24T16:26:23Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-f9b137e5ebbd4b2fba8b127ac6e303d32024-03-31T04:37:19ZengElsevierMolecular Metabolism2212-87782024-04-0182101906Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic miceKanikkai Raja Aseer0Caio Henrique Mazucanti1Jennifer F. O’Connell2Isabel González-Mariscal3Anjali Verma4Qin Yao5Christopher Dunn6Qing-Rong Liu7Josephine M. Egan8Máire E. Doyle9Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USALaboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USALaboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USAInserm UMR1190 - Translational Research of Diabetes, Pôle recherche 3ème Ouest, 1, place de Verdun 59045 Lille Cedex, FranceDepartment of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USALaboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USALaboratory of Molecular Biology & Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USALaboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USALaboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USALaboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Corresponding author.Objective: Type 1 diabetes (T1D) occurs because of islet infiltration by autoreactive immune cells leading to destruction of beta cells and it is becoming evident that beta cell dysfunction partakes in this process. We previously reported that genetic deletion and pharmacological antagonism of the cannabinoid 1 receptor (CB1) in mice improves insulin synthesis and secretion, upregulates glucose sensing machinery, favors beta cell survival by reducing apoptosis, and enhances beta cell proliferation. Moreover, beta cell specific deletion of CB1 protected mice fed a high fat high sugar diet against islet inflammation and beta cell dysfunction. Therefore, we hypothesized that it would mitigate the dysfunction of beta cells in the precipitating events leading to T1D. Methods: We genetically deleted CB1 specifically from beta cells in non-obese diabetic (NOD; NOD RIP Cre+ Cnr1fl/fl) mice. We evaluated female NOD RIP Cre+ Cnr1fl/fl mice and their NOD RIP Cre− Cnr1fl/fl and NOD RIP Cre+ Cnr1Wt/Wt littermates for onset of hyperglycemia over 26 weeks. We also examined islet morphology, islet infiltration by immune cells and beta cell function and proliferation. Results: Beta cell specific deletion of CB1 in NOD mice significantly reduced the incidence of hyperglycemia by preserving beta cell function and mass. Deletion also prevented beta cell apoptosis and aggressive insulitis in NOD RIP Cre+ Cnr1fl/fl mice compared to wild-type littermates. NOD RIP Cre+ Cnr1fl/fl islets maintained normal morphology with no evidence of beta cell dedifferentiation or appearance of extra islet beta cells, indicating that protection from autoimmunity is inherent to genetic deletion of beta cell CB1. Pancreatic lymph node Treg cells were significantly higher in NOD RIP Cre+ Cnr1fl/fl vs NOD RIP Cre− Cnr1fl/fl. Conclusions: Collectively these data demonstrate how protection of beta cells from metabolic stress during the active phase of T1D can ameliorate destructive insulitis and provides evidence for CB1 as a potential pharmacologic target in T1D.http://www.sciencedirect.com/science/article/pii/S2212877824000371Beta cell apoptosisBeta cell proliferationCannabinoid 1 receptorInsulitisIslet of LangerhansType 1 diabetes |
| spellingShingle | Kanikkai Raja Aseer Caio Henrique Mazucanti Jennifer F. O’Connell Isabel González-Mariscal Anjali Verma Qin Yao Christopher Dunn Qing-Rong Liu Josephine M. Egan Máire E. Doyle Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice Molecular Metabolism Beta cell apoptosis Beta cell proliferation Cannabinoid 1 receptor Insulitis Islet of Langerhans Type 1 diabetes |
| title | Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice |
| title_full | Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice |
| title_fullStr | Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice |
| title_full_unstemmed | Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice |
| title_short | Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice |
| title_sort | beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non obese diabetic mice |
| topic | Beta cell apoptosis Beta cell proliferation Cannabinoid 1 receptor Insulitis Islet of Langerhans Type 1 diabetes |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824000371 |
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